Rates of syphilis continue to increase in the United States and HIV-infected patients make up a large proportion of cases. The interaction between syphilis and HIV is complex and still incompletely understood. Although diagnosis and management of HIV-infected patients with syphilis is, in general, similar to HIV-uninfected patients, the former may be at increased risk for complications. Recent data suggest that HIV-induced immunosuppression may alter the course of syphilis and that highly active antiretroviral therapy may have a beneficial effect on syphilis outcomes. Prevention strategies consisting of sexual risk assessments, condom use, treatment of infected partners, yearly screening for syphilis of all HIV-infected patients, and enhanced clinical and serologic follow-up of treated HIV-infected patients are critical components of a comprehensive approach to care.