In 1478 Pope Sixtus IV sent a letter to Fernando and Isabel regarding the Judaizing of certain baptized people and their presumed influence on others to follow suit; this letter apparently was a response to a previous communication on this score from the Catholic monarchs. Complying with their request for sanction to act against heretics, the pope authorized the appointment of inquisitors in certain cities. By the end of 1480 Fernando and Isabel had taken steps to implement the Inquisition in Seville and by early 1481 the Santo Oficio or Holy Office was in place in that city (Roth 222-23).

The libelous accusations that Jews scourged the crucifix were so common that the Inquisitors incorporated it into their questions, asking if anyone had witnessed such an act (Baer II: 362). It was also a popular superstition throughout Europe that Jews desecrated the host, and in 1377 several Jews were tortured and burnt to death in Huesca on this charge (Baer II: 88-89). As Reay Tannahill records in Flesh and Blood, in 1215, Pope Innocent III summoned the Fourth Lateran Council which declared that the host not only symbolized the body of Christ, but was transubstantiated such that «hoc est corpeum meum», 'this is my body' was to be interpreted literally (77). Tannahill further notes that «Within a few decades, Christians had become so convinced that the host was the real and sentient body of Christ that they were prepared to massacre Jews accused of torturing it» (82). She cites a dozen cases in thirteenth and fourteenth-century Europe where entire Jewish communities were annihilated for allegedly tormenting consecrated wafers (83-84).

In Jewish Self-Hatred, Sander Gilman discusses the history of the myth of the foetor judäicus (174-75).

At times 1492 loses its narrative focus on Juan Cabezón and lapses into long digressions on the Inquisition, to the extent that Campos considers the Inquisition to be the central protagonist of Aridjis's novel. Campos observes that the ultimate effect of the novel's focus on the Inquisition is to alienate Juan Cabezón's perspective from his own personal story, thus marginalizing him once again.

Because it was an organ of the Catholic church, the Inquisition had no jurisdiction over Jews as such. Their efforts to eradicate heresy, however, were often directed toward Jews who had submitted to voluntary or forcible baptism and later recanted. While the terms converso and crypto-Jew are often conflated in common parlance, they are not interchangeable: the term converso or New Christian simply refers to someone of Jewish extraction who has undergone baptism, while crypto-Jew properly indicates a baptized Jew who 'judaizes' or practices Jewish rites and customs in secret.

Roth claims that although modern historians have repeatedly exaggerated Pulgar's claim, the presumed Jewish ancestry of Tomás de Torquemada would have been quite remote (225).

Aridjis's novel defines the familiars as an army of unpaid spies who serve the inquisitors in exchange for material privileges; they have permission to bear arms and are empowered to arrest heretics (149).

Pedro de Arbués was attacked by two men with covered faces in 1485 while praying matins in a church in Zaragoza. Implicated in this notorious assassination were many principal conversos, including relatives of Luis de Santángel and Gabriel Sánchez, two converso treasury officials who were involved in arranging the financing of Columbus's first voyage.

Clara's father is presumably Luis de Santángel, the merchant of Teruel who was tried by the Holy Tribunal in the mid-1480s. Roth notes that the historical Santángel of Teruel is not to be confused either with the Luis de Santángel who was accused in connection with the Arbués murder in Zaragoza, nor with the Catholic Monarch's treasury official of that same name (130).

The La Guardia trial was an extreme example of the common blood libel that Jews ritually murder Christian children. In this case, no body representing the child who was allegedly crucified was ever produced; moreover, no effort was made to link the «holy child» to any particular missing child. Yitzhak Baer documents the La Guardia trial extensively, recounting the detailed testimony of alleged conspirator Yucé Franco, who admitted to crimes under torture; Franco was burned with several others in an auto, in spite of the fact that he was a Jew rather than a converso and thus was not subject to the inquisitorial charge of heresy (II: 398-423). Henry Charles Lea observes that in light of the lack of evidence and the discrepancies in the various depositions, it is evident that the entire affair was «the creation of the torture-chamber» (1: 134).