In the early sixteenth century, syphilis spread throughout Europe. "If leprosy of the Early Middle Ages was a metaphor and paradigm of social exclusion and civil death, if the plague of the Late Middle Ages was a metaphor and paradigm of physical death and fear of dying, syphilis was a symbol of the Renaissance and the model of a sinful and shameful disease", transmitted sexually (Cosmacini p. 231).

Girolamo Fracastoro (1478-1553) named the disease in Syphilis siue morbus gallicus in 1530, held in the Library of Pharmaceutical and Pharmacological Sciences of the University of Padova (digital copy). A poet as well as a physician, the author invents a mythological origin, in which the disease is a punishment of Apollo against the conceit of a shepherd, Syphilus. Fracastoro put forward the theory, now disputed, that syphilis arrived in Europe from the newly "discovered" America. He also called it the French disease, referring to its transmission, at the outset of the Italian Wars in 1493, from the Spanish army to the French army in the battle for Naples. Fracastoro proposed prevention based on a modest, healthy lifestyle and suggested mercury and guaiacum, an American plant, as medications. The Veronese doctor identified the microscopic contagions, seminaria, in De contagione e contagionis morbis, held in the Library of Pharmaceutical and Pharmacological Sciences of the University of Padova in the 1555 edition of his complete works (digital copy).

Fallopius (1523-1562) wrote about syphilis, De morbo gallico, published in Padua after his death, of which the Library of Pharmaceutical and Pharmacological Sciences of the University of Padova has a 1564 reprint of the first edition from the previous year. Fallopius opens with a moralistic observation: "Deus saepe morbis castigavit peccata nostra" (God often punishes our sins with diseases) (c. 1r), but goes straight to the scientific review of the now universal disease "invadentes nunc Italiam, nunc alias vel Europae, vel caeterarum mundi partium regiones" (c. 1r). He discusses the different names of syphilis (French disease to Italians but Neapolitan disease to the Spanish), defines the symptoms with precision (De signis) and their complex sequencing (De numero symptomatum Gallicum sequentium atque de ordine), and analyses the difficult aetiological background of the ailment (De causis). With regards to the origins of the disease, Fallopius points a finger against the widely held view of an unfortunate astral conjunction: "medicus... potest magis cantaros, et urinales contemplari quam caelum" (that doctors contemplate the chamber pots and urinals instead of the sky) (c. 5r). The cause of the disease is found in sexual contagion "non aquam, non aerem, nec locum, sed actiones hominum" (c.7r e v). For the cure, along with the suggestion to strengthen the body, and therefore the immune system, Fallopius proposes remedies then in use, from mercury inhalations (hydrargyror) to decoctions of guaiacum, or holy wood. The closing chapter is about prevention (De praeservatione), which proposes abstinence or the use of prophylactics (linteolum imbutum medicamento, linen cloth soaked in a drug, c. 52r), described here for the first time in print.

The reference work for the treatment of syphilis was Liber de morbo Gallico by Niccolò Massa (1489-1569), published in Venice in 1536, one of the first organic treatises on the subject which examines the symptoms and remedies for the illness (digital copy). Bound with this work, the Library of Pharmaceutical and Pharmacological Sciences of the University of Padova holds his Liber de febre pestilentiali, ac de pestichiis, morbillis, variolis, & apostematibus pestilentialibus, published in Venice in 1540 (digital copy). In 1535, Massa was commissioned by the Venetian health authorities to investigate the nature of the epidemic spreading to cities, and in the book, he explains how to distinguish the symptoms of the plague, based as well on that experience. His diagnostic skills of the two epidemics made him renowned and sought out throughout Europe, allowing him to build a fortune.

Syphilis caused 20 million deaths. It was not until the early twentieth century that the Paul Ehrlich laboratory found an effective remedy for syphilis in Salvarsan, of which the Library of Pharmaceutical and Pharmacological Sciences of the University of Padova has a vial donated by Ehrlich, now exhibited in the Museum of the History of Medicine MUSME in Padua. The discovery of penicillin in 1940 took its place for its efficacy and the absence of side effects.