Syphilis has been a public health problem for centuries. Syphilis and HIV form a dangerous combination: syphilis significantly increases the risk of contracting HIV infection, and HIV can alter the natural course of syphilis. Despite a better understanding of the interaction between these two diseases, many controversies persist. The incidence of syphilis has increased among HIV-infected patients both in Europe and in the USA, and especially in the homosexual/bisexual transmission group. We discuss the interaction between HIV/AIDS and syphilis in a review of the most recent literature, focusing particularly on the diagnosis, treatment, and follow-up of HIV-infected patients with syphilis. Early diagnosis of syphilis in HIV-infected patients requires awareness among both patients and clinicians. Early treatment of syphilis is crucial as it reduces the risk of transmission.