The current study presents some aspects of syphilis in the Balkan Peninsula from the 19th century until the Interwar. Ever since the birth of modern Balkan States (Greece, Bulgaria, Turkey and Serbia), urbanization, poverty and the frequent wars have been considered the major factors conducive to the spread of syphilis. The measures against sex work and sexually transmitted diseases (STDs) were taken in two aspects, one medical and the other legislative. In this period, numerous hospitals for venereal diseases were established in the Balkan countries. In line with the international diagnostic approach and therapeutic standards, laboratory examinations in these Balkan hospitals included spirochete examination, Wassermann reaction, precipitation reaction and cerebrospinal fluid examination. Despite the strict legislation and the adoption of relevant laws against illegal sex work, public health services were unable to curb the spread of syphilis. Medical and social factors such as poverty, citizen's ignorance of STDs, misguided medical perceptions, lack of sanitary control of prostitution and epidemiological studies, are highlighted in this study. These factors were the major causes that helped syphilis spread in the Balkan countries during the 19th and early 20th century. The value of these aspects as a historic paradigm is diachronic. Failure to comply with the laws and the dysfunction of public services during periods of war or socioeconomic crises are both factors facilitating the spread of STDs.