BACKGROUND: Syphilis rates are rising in California, but the impact of HIV infection on syphilis infection remains uncertain. We describe differences between HIV-infected and HIV-uninfected patients diagnosed with syphilis within Kaiser Permanente Northern California. METHODS: We performed retrospective analyses of patients diagnosed with incident syphilis from 1995 to 2005 (622 cases/9989 HIV-infected patients and 3584/4,442,780 HIV-uninfected). Among cases, we ascertained demographic, clinical characteristics, and laboratory (including baseline labs and repeated RPR titers) data. We performed Poisson regression (incidence) and Cox proportional hazard modeling (reduction in RPR and serologic failure after syphilis therapy) adjusting for age, gender, and HIV status and among HIV-infected cases only by use of antiretroviral therapy (ART). RESULTS: HIV-infected patients had incident syphilis rates of 62.3/1000 person-years compared with 0.8/1000 HIV-uninfected patients, corresponding to an adjusted rate ratio of 86.0 (P <0.001); rate differences increased significantly over time. HIV-infected patients had a greater likelihood of reduction in RPR and serologic failure after syphilis therapy (HR = 2.5 and 2.6 respectively [P <0.001 both]). Among HIV-infected only, patients on ART had lower rates of infection but higher likelihood of reduction in RPR after syphilis therapy and serologic failure compared with patients not on ART. CONCLUSIONS: HIV-infected patients had greater rate of incident syphilis compared with HIV-uninfected, a disparity which increased over time. HIV-infected patients had greater likelihood of decline in RPR and serologic failure. HIV-infected patients should be screened for syphilis regularly.