Syphilis is a sexually transmitted infection with various stages of evolution and a myriad of presentations. To avoid a delay in diagnosis, it is important to recognize secondary syphilis presenting with vesicular lesions. A patient presented with maculopapular rash of recent onset with several vesicles and related the eruption to paracetamol taken one day before. The differential diagnoses considered were drug eruption, pityriasis lichenoides et varioliformis acuta, pityriasis rosea and secondary syphilis. HIV, VDRL (1:256) and TPHA tests were positive and histopathology revealed lymphohistiocytic infiltrate and plasma cells. Thus, a diagnosis of secondary syphilis coexisting with HIV was confirmed. The patient was administered benzathine penicillin and anti-retroviral therapy was started. He responded very well to treatment. We report this case because of the rarity of vesicular eruption in secondary syphilis.