Although the annual incidence of primary and secondary syphilis has dropped to the lowest rate recorded, syphilis remains an important cause of ocular disease. Uveitis is the most common ocular manifestation of syphilis in both HIV-positive and HIV-negative patients, and the diagnosis should prompt an analysis of the cerebrospinal fluid to exclude associated neurosyphilis. Newer modalities such as enzyme immunoassays and genomic amplification using the polymerase chain reaction may prove to be useful techniques to detect Treponema pallidum in intraocular specimens. The preferred treatment for all stages of syphilis remains parenteral penicillin G, although the preparation, dose, route of administration, and duration of therapy are dictated by the stage of disease and various host factors. All patients diagnosed with ocular syphilis should be tested for HIV, because the presence of a primary genital chancre increases the risk of acquiring or transmitting HIV, and because risk factors for the two diseases are similar.