The aim of this study was to analyze the characteristics and clinical manifestations of secondary syphilis among patients registered at the City Institute for Skin and Venereal Diseases in Belgrade, during the period from 2010 to 2014. The study was designed as a case-note review. In the five-year period, a total of 62 patients with secondary syphilis were registered. The average patient age was 32 years. There were 45 (72.6%) HIV-negative, and 17 (27.4%) HIV-positive patients. The incidence of HIV–positive patients was significantly different from random distribution (p = 0.016). All HIV-positive patients were unmarried men. A significant percentage of HIV-positive patients were unemployed (p < 0.001), reported unknown source of infection (p = 0.002) and were all homosexuall (p = 0.026). More than 25% of all patients with syphilis had a history of chancres, and it was still present at the time of examination in 11.3% of all patients. The majority of cases (87.1%) had a rash, and lymphadenopathy was found in 20% of patients. However, syphilitic alopecia was detected only in HIV-positive cases (p = 0.004). There were no statistically significant differences between HIV-positive and HIV-negative patients in regard to other clinical manifestations, such as mucous patches and condylomata lata. Being a great imitator, secondary syphilis may manifest in a myriad of diverse morphological entities and clinical manifestations. We review a range of cutaneous manifestations of secondary syphilis and skin diseases it may mimic. Clinicians must be vigilant and consider syphilis in differential diagnosis, and maintain a high index of suspicion, especially when assessing vulnerable populations, such as men who have sex with men and HIV-infected individuals.