The authors describe the emergence of syphilis in Dalmatia, the coastal part of Croatia, at the very end of the 15th and the beginning of the 16th century, its presence up to the 20th century, making reference to the most important physicians that tried to cure the new disease. The archives of Dalmatian towns, their statutes, some literary works, travel writers, physician books, and articles by historians of medicine contain data on syphilis in Dalmatia. Syphilis was first observed in Zadar (1500), Trogir (1501) and Dubrovnik (1502). Among the first physicians who treated patients in Dubrovnik were Mariano Santo and Amatus Lusitanus. The latter was the first to make prosthesis for the palate defect to cure tertiary syphilis lesions. According to the statutes of Dalmatia towns, each had one or more paid physicians and pharmacists. The Ottoman travel writer Evlija Celebi gave an account of syphilis in Dalmatia in the 17th century. At the end of the 18th century and during the 19th century, endemic syphilis known as morbus de Scherlievo and morbus Brenensis appeared in Dalmatia. Because of the numerous cases observed in the region, new hospitals were opened in Dalmatian towns and the patients were hospitalized. Among the physicians who were engaged in the fight against syphilis in the 19th century, mention should be made of Giovanni Battista Cambieri, Nikola Selak and Božo Peričić. They all treated the affected patients and described syphilis and ‘Scherlievo disease’in Croatian as well as in other languages. Syphilis was present in Dalmatia towns during the 15th-20th century, remaining a challenge and arousing the interest of current dermatovenereologists as well as other specialists