Mateo is a Holy Inquisition outlaw who returns to Seville five years after fleeing, in order to honour a promise -to rescue Valerio Huertas, the bastard son of his friend Germán Larrea, who died while he was away. To avoid being spotted by the Holy Office, Mateo hides in the house of his former partner in crime Luis de Zúñiga, a nouveau riche who tries to keep the plague in secret, quarantined in the outskirts of the city, outside the walls, where the first cases were found.

Mateo is asked by Inquisitor General Celso de Guevara to find the murderer of one of the most important traders of the city, Ignacio Azuaga. If he gets him, the Holy Office will forgive him and Mateo will save his life. Mateo accepts and forces Valerio to move with him into the house of Zúñiga, who tries to corrupt the Council to prevent the plague, which has already entered the city, from being publicly announced. During the course of the investigation, Mateo meets the widow of his friend Germán, Teresa, a painter who is forced to sign her works with her father's name in order to sell her paintings, and who seems to have found inspiration in a ragged prostitute, Eugenia.

The dead body of another woman appears in the harbour of the city. It is Lucina Utrera, the daughter of Captain Utrera. Like Azuaga, she was impaled and drained of blood. Mateo discovers that the two murders have links with his old printers. His sleeplessness and his sinister hallucinations take a turn for the worse. Teresa hires Eugenia at her husband's factory, in spite of the resistance of the other workers, all men, and the warnings of her Administrator. In their view, only a man can manage the factory. The father of Leandra, Valerio's girlfriend, and Morata, one of the Twenty-Four members of the Council Zúñiga has bribed, dies from the plague. The government is forced to announce the plague publicly and to close the city.

The plague devastates the city. Mateo and Valerio find the missing lover of Ignacio Azuaga, Carmen Gálvez, who confirms to them that Ledesma, the Protestants' secret leader, seems to be behind all the murders. In his attempt to keep the harbour open, Zúñiga manages to become a member of the Council of the Twenty-Four. Eugenia is the victim of a rape attempt at the factory and Teresa intervenes by firing the master and almost all the workers. As a consequence, Teresa is assaulted and violently humiliated in the street. A new dead body appears -Alejandro de Dresdner, Treasurer of the Mint and Zúñiga's main financial support. His murder also bears Ledesma's signature. Leandra catches the plague.

Mateo and Valerio exhume Germán's corpse and corroborate he was also murdered by Ledesma. Zúñiga takes advantage of the plague, the famine and the popular uprisings to negotiate with the Assistant and persuade him to open the city's harbour to allow the fleet from America to unload the shipments. The Council closes down Teresa's factory against her will, whilst Mateo and Valerio discover Ledesma's secret identity as they manage to track him down. Ledesma commits suicide when he finds himself surrounded by Inquisition soldiers, with no way out. Leandra dies, and Valerio demands that Mateo keeps the word he gave to his father and take him to the New World.

The epidemic starts to decline. Inquisitor General Celso de Guevara hands Mateo the bull, granting his freedom, thereby settling the case. As a result of Mateo's investigation, Zúñiga is arrested for collaborating with Protestants and sentenced by the Inquisition to burn at the stake in a spectacular auto-da-fé, which the Inquisition uses for propaganda purposes. The Council is firm with Teresa, unless she appoints a man to manage the factory, the latter will be definitely closed down and she will be jailed. During the auto-da-fé, while the city demands heretics to be sacrificed, Mateo discovers that Ledesma was not the real murderer.