Piero di Cosimo acquires a reputation for eccentricity—a reputation enhanced and exaggerated by later commentators such as Giorgio Vasari, who includes a biography of Piero di Cosimo in his Lives of the Artists.

Reportedly, he was frightened of thunderstorms, and so pyrophobic that he rarely cooked his food; he lived largely on hard-boiled eggs, which he prepared fifty at a time while boiling glue for his artworks.

He also resisted any cleaning of his studio, or trimming of the fruit trees of his orchard; he lived, wrote Vasari, "more like a beast than a man".

If, as Vasari asserts, he spent the last years of his life in gloomy retirement, the change was probably due to preacher Girolamo Savonarola, under whose influence he turned his attention once more to religious art.

The death of his master Roselli may also have had an impact on Piero's morose elder years.

The Immaculate Conception with Saints, at the Uffizi, and the Holy Family, at Dresden, illustrate the religious fervor to which he was stimulated by Savonarola.