At CERN, Father Silvano and Dr. Vittoria Verna create three canisters of antimatter. Silvano is murdered, and one of the canisters is stolen. The Roman Catholic Church mourn the sudden death of Pope Pius XVI, and prepare for the papal conclave to elect his successor in Vatican City. Father Patrick McKenna, the Camerlengo, takes control of the Vatican. Four of the “preferiti”, the favoured candidates to be Pope, are kidnapped by a man claiming to represent the Illuminati. He sends the Vatican a warning, claiming he will murder each of the cardinals from 8pm to midnight, where the stolen antimatter will explode and destroy the city, hidden somewhere within.

American symbologist Professor Robert Langdon is brought to the Vatican to help. He deduces that the four cardinals will be murdered on the four altars of the “Path of Illumination”, in locations relevant to the classical elements. McKenna gives Langdon access to the Vatican Secret Archives to research the altars, against the wishes of Commander Richter, head of the Swiss Guard. He and Vittoria examine Galileo Galilei’s banned book, following clues to the Chigi Chapel, accompanied by Ernesto Olivetti and Claudio Vincenzi of the Corps of Gendarmerie of Vatican City. They find Cardinal Eber dead, branded with the ambigrammatic word “Earth”.

The second, Cardinal Lamassé, is murdered in St. Peter’s Square, his lungs punctured and branded with “Air”. Vittoria suspects the Pope was actually murdered via overdose, she and McKenna confirming this by secretly inspecting his body. Langdon, Olivetti, and Vincenzi eventually identify the Santa Maria della Vittoria as the altar of fire, finding Cardinal Guidera burning to death, branded with “Fire”. The assassin appears, killing Olivetti and Vincenzi, before escaping to drown Cardinal Baggia in the Fontana dei Quattro Fiumi. Langdon and civilians intervene, rescuing Baggia, who tells Langdon the preferiti were held in Castel Sant’Angelo.

Richter confiscates Dr. Silvano’s journals, Vittoria convinced that he is a conspirator. Langdon, Vittoria, and the police storm Castel Sant’Angelo. Langdon and Vittoria find the assassin’s lair, discovering five brands, the last meant for McKenna. The assassin escapes, claiming his contractors are “men of God”. Guided to a car by his unseen contractor, the assassin dies when the vehicle explodes upon ignition. Langdon and Vittoria find a secret passageway leading to the Vatican, warning the Swiss Guard of McKenna’s fate. They find Richter hovering over a branded McKenna. He, and Archbishop Simeon, an alleged conspirator, are killed. Langdon retrieves a key from the dying Richter’s hand.

The antimatter container is found in Saint Peter's tomb, but will detonate in five minutes, the cold temperature preventing its battery from being charged in time. McKenna flees the Vatican with the canister, piloting a helicopter into the sky, then parachutes out seconds before the antimatter detonates. McKenna is hailed as a hero, with calls for him to be elected as Pope.

Langdon and Vittoria retrieve Silvano’s journals from Richter’s office, finding he kept tabs on the Pope with hidden security cameras. They find footage of Richter confronting McKenna, revealing the Camerlengo is the mastermind behind the attacks. The Pope had invited Silvano to publicly present the antimatter as proof of a divine power, bridging the gap between religion and science. Considering such a claim blasphemy, McKenna orchestrated the Pope’s death, and the Illuminati assassin, then plotted to be elected as Pope. The footage is shown to the papal conclave. McKenna, realising he has been exposed, commits suicide via self-immolation.

The Vatican announces McKenna died from injuries from his parachute landing, and Baggia is elected as Pope Luke I. Cardinal Strauss, the Pope’s new Camerlengo, gives Langdon the “Diagramma Veritatis” as thanks for his help, and to complete his scholarly work on Galileo. The new Pope gives Langdon and Vittoria a thankful nod, before stepping out on the balcony to greet the crowd below.

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