Syphilis is a complex disease, which is sexually transmitted. The incidence of syphilis is rising all over the world, partly due to the increased transmission in HIV patients and other high risk groups such as men who have sex with men. Interestingly syphilis itself facilitates HIV infection in several ways. Great importance exists in recognition of both diseases and their complex interactions. This article will review the manifestations of syphilis in the context of HIV infected patients, and the challenging diagnosis and management of these patients.