Syphilis and HIV infections frequently occur simultaneously because they affect the same risk groups. The declining incidence of syphilis during the 1990s reversed beginning in 2001, with most of the new cases occurring in men who have sex with men. This group is at highest risk of having or acquiring HIV infection. The clinical presentation of syphilis may be altered in persons with HIV infection and the response to therapy may be affected by immunosuppression. Syphilis may also subtly affect HIV infection, at least transiently. This article reviews the epidemiology, clinical manifestations, and treatment of syphilis in the setting of HIV infection.