Syphilis is still a common disease in many countries. The clinical features of secondary syphilis are well documented, and the histopathological features of secondary syphilis have been reviewed in a few studies. The present study documents the histopathology of secondary syphilis based on 68 skin biopsies from 38 patients. Based on the findings of this study, and a review of the literature, diagnostic guidelines are suggested and the differential diagnoses are discussed.