In the dramatic and restless years that Castiglione spent in Spain, first the Duchess of Urbino, Elisabetta Gonzaga (28th January 1526), died, and then Emilia Pio (20th May 1528). These were for Baldassarre the signs that the epoch in which he had been a protagonist was now coming to an end. On 11th July 1528, in a similar mood, he wrote a brief letter in Latin to his three children, Camillo, Anna and Ippolita, whom he had not seen for four years. The text was in the nature of a spiritual testament, and its serenity announced a goodbye. This was visible in the final words, which he directed particularly to his first born Camillo, steeped in a strong self awareness and a limpid perception of destiny: “Disce puer virtutem ex me verumque laborem. Fortunam ex aliis” (= “Learn from me, dear boy, virtue and perseverance in work. Fortune from someone else”; in V. Cian, Nel mondo di Baldassarre Castiglione, “Archivio storico lombardo”, 7, 1942, 89).
In the same months the Emperor Charles V, in a final gesture of good faith and respect, offered him the bishopric of Avila, that Castiglione declared he could not accept as long as the troubles between the Emperor and the Pope were not definitively resolved. In January 1529 Clemente VII transmitted to the nuncio his permission, so, without further ado, the solemn investiture took place, providing honour and comfort for Castiglione.
On 2nd February 1529, however, at Toledo, exhausted by the clash with Valdés and by the troubles and the physical and moral travails of recent times, Baldassarre was struck by violent fevers, that on 8th February, little more than fifty years old, brought about his death. He was buried in the cathedral of the city; all the dignitaries, ecclesiastic and lay, from the Imperial Court, and a great crowd, followed the funeral ceremonies solemnly. Charles V publicly mourned his loss in front of the court and his nephew, Tommaso Strozzi, his secretary and executor of his will.