In recent decades, a rising rate of syphilis infection, often in association with HIV, has been recorded in Europe. In the first years following their appearance, syphilis and HIV shared the character of "new", challenging and serious diseases. The prime example of a "new disease", syphilis appeared between the end of the Middle Ages and the beginning of the Renaissance period, a time in which medicine was changing from a dogmatic to an experimental discipline. Luigi Luigini's collection of all the works on syphilis that had appeared to date (1566) offers a unique and significant insight into the discussion of the novelty of this disease, even after half a millennium.