At the University of Padua Fracastoro was a colleague of the astronomer Copernicus. As a physician, he maintained a private practice in Verona. He is best-known for “Syphilis sive morbus Gallicus” (1530; “Syphilis or the French Disease”), a work in rhyme giving an account of the disease, which he named. He made an intense study of epidemic diseases, and, while in the service of Pope Paul III at the Council of Trent (1545–63), he provided the medical justification for the removal of the council to the papal state of Bologna by pointing out the danger of plague in the north Italian town of Trent.

Fracastoro outlined his concept of epidemic diseases in De contagione et contagiosis morbis (1546; “On Contagion and Contagious Diseases”), stating that each is caused by a different type of rapidly multiplying minute body and that these bodies are transferred from the infector to the infected in three ways: by direct contact; by carriers such as soiled clothing and linen; and through the air. Although microorganisms had been mentioned as a possible cause of disease by the Roman scholar Marcus Varro in the 1st century BC, Fracastoro's was the first scientific statement of the true nature of contagion, infection, disease germs, and modes of disease transmission. Fracastoro's theory was widely praised during his time, but its influence waned, and it fell into general disrepute until an experimental version was later elaborated by German physician Robert Koch and French chemist Louis Pasteur.