By the treaty of Cambrai, in 1529, Francis I abandoned the Milanese to Charles V and it thenceforth formed part of the Italian possessions of Spain. In the eleventh and twelfth centuries it had been the hot-bed of heresy and it was, in the thirteenth, one of the earliest scenes of inquisitorial activity. It was there that Pietro di Verona sealed his devotion with his blood and became the patron saint of the Holy Office. With the gradual extermination of heresy, the Inquisition there as elsewhere grew inert and, even after the new and threatening development of the Reformation, when Paul III, in 1536, was alarmed by reports of the proselyting zeal and success of Fra Battista da Crema, he had no tribunal on which he could rely to suppress the heretic. In default of this he commissioned Giovanni, Bishop of Modena, who was then in Milan, together with the Dominican Provincial, to preach against the heretics and to punish according to law those whom they might find guilty, at the same time significantly forbidding the inquisitor and the episcopal Ordinary to interfere.

Even when the Inquisition was reorganized by Paul III, in 1542, it was for some time inefficiently administered and lacked the secular support requisite to its usefulness. This was especially felt in the Milanese which, from its neighborhood to Switzerland and the Waldensian Valleys, was peculiarly exposed to infection.