The plot follows Harvard symbologist Robert Langdon, as he tries to stop what seems to be the Illuminati, a legendary secret society, from destroying Vatican City with the newly discovered power of antimatter.
CERN director Maximilian Kohler discovers one of the facility's most respected physicists, Leonardo Vetra, murdered in his own secured, private quarters at the facility. His chest is branded with a symbol—an ambigram of the word "Illuminati"—and one of his eyes has been removed. Instead of calling the police, Kohler contacts Robert Langdon, whom he has determined through his research is an expert on the Illuminati. Kohler requests his assistance in uncovering the murderer.
Langdon determines that the ambigram is authentic, which means that the secret society of legend, long thought to be extinct, has apparently resurfaced. Kohler calls Vetra's adopted daughter Vittoria to the scene, and it is later revealed that the Illuminati have also stolen a canister containing a quarter of a gram of antimatter—an extremely dangerous substance with immense destructive potential comparable to a small nuclear weapon, a potential unleashed upon contact with any form of normal matter. When charged with electricity at CERN, the canister's magnetic field controls the drop of antimatter to float suspended in a high vacuum, ensuring safety; but when it was taken away from its electricity supply, it automatically switched to its back-up battery, which will only power it for 24 hours, at which point the antimatter will fall, come into contact with the base of the canister, and self-destruct. The Illuminati have placed the stolen canister somewhere in Vatican City, with a security camera in front of it, as its digital clock counts down to the explosion.
Langdon and Vittoria make their way to Vatican City, where the Pope has recently died, and the papal conclave has convened to elect the new pontiff. Cardinal Mortati, host of the election, discovers that the four Preferiti, cardinals who are considered to be the most likely candidates in the election, are missing. After they arrive, Langdon and Vittoria begin searching for the Preferiti in hopes that they will also find the antimatter canister in the process. Their search is assisted by Camerlengo Carlo Ventresca (the late pope's closest aide) and the Vatican's Swiss Guard, including Commander Olivetti, Captain Rocher, and Lieutenant Chartrand.
Convinced that the Illuminati are in some way responsible for the disappearance of the Preferiti, Langdon attempts to retrace the steps of the so-called "Path of Illumination", an ancient and elaborate process once used by the Illuminati as a means of induction of new members; prospective candidates for the order were required to follow a series of subtle clues left in various landmarks in and around Rome. If the candidate followed the clues properly, he would be able to locate the secret meeting place of the Illuminati and be granted membership in the order. Using his extensive knowledge of religious and occult history, Langdon sets off on the Path of Illumination in hopes of uncovering clues as to the disappearance of the Preferiti and the location of the antimatter canister.
Bernini's Habbakuk and the Angel, and Agostino Chigi's pyramidal wall tomb.
The Path leads Langdon to four major locations in Rome (Vatican City is within the city of Rome), each associated with what the Illuminati believed to be the four primordial elements of all things in existence: 'Earth', 'Air', 'Fire', and 'Water'. Upon arriving at each location, Langdon finds one of the Preferiti murdered in a fashion appropriate to the location's respective element: The first cardinal was branded with an Earth ambigram, had soil forced down his throat and was buried; the second was branded with an Air ambigram and had his lungs punctured; the third was branded with a Fire ambigram and was burned alive; and the fourth was branded with a Water ambigram and was chained and left to drown at the bottom of a large fountain.
West Ponente at Saint Peter's Square.
After finding the bodies of the first two Preferiti (Earth and Air), Langdon hurries to the Santa Maria della Vittoria Basilica and finds the Preferiti's abductor in the act of setting the third cardinal on fire. The kidnapper, who is also responsible for Leonardo Vetra's murder and the theft of the antimatter canister, is an unnamed assassin who is working under the orders of the Illuminati master "Janus", whose true identity is unknown. Commander Olivetti is killed, and Langdon nearly dies himself in this encounter with the assassin, who manages to kidnap Vittoria. Langdon manages to escape and meets the assassin yet again at the final element's landmark (Water), but is unable to save the final cardinal.
Ecstasy of St Teresa.
Langdon nevertheless attempts to complete the Path of Illumination in order to find the assassin and rescue Vittoria. His search leads him to Castel Sant' Angelo, that hides an underground tunnel leading directly into the pope's chambers in the Vatican. Langdon frees Vittoria, and together they send the assassin falling several hundred feet to his death. The two hurry back to St. Peter's Basilica, where they find that Kohler has arrived to confront the camerlengo in private. Langdon and Vittoria fear that Kohler is Janus, and that he has come to murder the camerlengo as the final step in his plot against the Church. Hearing the camerlengo scream in agony from being branded with the Illuminati Diamond, the Swiss Guards burst into the room and open fire on Kohler. Captain Rocher is also killed by Lieutenant Chartrand after being accused of being an Illuminatus by the Camerlengo. Just before he dies, Kohler gives Langdon a videotape that he claims will explain everything.
The Fountain of Four Rivers.
With time on the canister running out, the Swiss Guard begins to evacuate the Basilica. As he is exiting the church, the camerlengo apparently goes into a trance and rushes back into the Basilica, claiming that he has received a vision from God revealing the location of the antimatter canister. With Langdon and a few others in pursuit, the camerlengo ventures deep into the catacombs beneath the Basilica and finds the canister sitting atop the tomb of Saint Peter. Langdon and the camerlengo retrieve the antimatter and get in a helicopter with only five minutes to spare. The camerlengo manages to parachute safely onto the roof of St. Peter's just as the canister explodes harmlessly in the sky. Langdon's fate is not immediately known, as there was not a second parachute on board the helicopter. The crowd in St. Peter's Square look in awe as the camerlengo stands triumphantly before them. Because of this "miracle", the papal conclave debate whether exception to Catholic law should be made to elect the camerlengo as the new Pope. Langdon managed to survive the explosion by using a window cover from the chopper as a parachute, and landed in the Tiber River near Tiber Island, which is famous for its reputation as an island blessed with miracles of healing. He is hurt, but not seriously.
Langdon returns to St. Peter's and views Kohler's tape with the College of Cardinals. Langdon, Vittoria, and the cardinals confront the camerlengo in the Sistine Chapel, where the truth is finally revealed; Shortly before the beginning of the novel, the Pope was scheduled to meet with Leonardo Vetra concerning his research at CERN. Vetra, a devout Catholic, believed that science was capable of establishing a link between Man and God, a belief that was manifested by his research on antimatter. Vetra's beliefs caused great discomfort to the camerlengo, who firmly believed that the Church alone, not science, should dictate the moral creed of the Christian faithful. While discussing Vetra, the pope reveals that his support is due to science having given him a son. Without waiting to hear the explanation (that the child was the result of artificial insemination), and horrified that the Pope appeared to have broken his vow of chastity, the camerlengo plots to "rectify" the situation. He poisoned the pope and, under the guise of an Illuminati master (Janus), he recruited the assassin, a killer fueled by the same zeal and animus towards the Church as his ancestors during the Crusades, to kill Vetra, steal the antimatter, and kidnap and murder the Preferiti just as the papal conclave was set to convene. The camerlengo planted the antimatter in St. Peter's, and feigned his last-minute vision, in order to be seen as a hero and the savior of Christendom by those who witnessed his brave acts. The Illuminati thus had no actual role in any of the novel's events, and its "involvement" was merely a plot engineered by the camerlengo to cover his own plans. As Langdon suspected from the very beginning, the Order of the Illuminati was indeed long extinct.
As one final twist, it is revealed that Camerlengo Ventresca himself was the birth son of the late pope, conceived through artificial insemination. Suddenly overcome with grief and guilt at having caused so much death, especially that of his own father, Ventresca soaks himself in oil and immolates himself before a crowd of onlookers in St. Peter's Square. The conclave elects Cardinal Mortati as the new pope. In an ironic twist, through a quibble, a loophole in the papal election process known as election by acclamation, two popes were chosen: Ventresca by all the cardinals cheering his name before he lights himself on fire, and Mortati through normal means.
Langdon and Vittoria retire to the Hotel Bernini. Lieutenant Chartrand delivers a letter and package to Langdon from the new pope. The package is the "Illuminati Diamond" brand, which is loaned indefinitely to Langdon. The story ends with Langdon and Vittoria about to engage in sexual intercourse.
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