Despite the widespread availability of effective treatment, the incidence of primary and secondary syphilis in the United States is on the rise. In addition, syphilis is occurring in a substantial number of patients infected with the human immunodeficiency virus (HIV), thus adding to the complexities of diagnosis and treatment. Primary syphilis represents a disseminated infection, often accompanied by abnormalities of the cerebrospinal fluid, that may pass unrecognized and progress to the myriad manifestations of secondary syphilis. The diagnosis of syphilis in patients with mucosal or skin lesions may be made by darkfield examination; once lesions have resolved, serologic tests are required. Patients with latent syphilis may have asymptomatic neurosyphilis and risk progression to tertiary disease. The diagnosis of asymptomatic neurosyphilis is necessary to determine the optimal treatment of patients with latent disease. The diagnosis of active neurosyphilis generally requires an inflammatory cerebrospinal fluid profile and a reactive cerebrospinal fluid VDRL test. Syphilis is common in HIV-infected patients, who may have an altered antibody response to infection and an apparent increased incidence of neurologic complications. The preferred treatment at all stages is penicillin, which is also the only recommended therapy for neurosyphilis. The optimal treatment of syphilis in HIV-infected patients is unknown.