HIV and syphilis are often seen as co-infections since they share a common mode of transmission. During episodes of syphilis, CD4 counts transiently decrease and HIV viral loads increase; however, the effect of syphilis co-infection on HIV disease progression (time to AIDS or death) is unclear. We analysed prospectively collected information on 2239 persons with estimated dates of HIV seroconversion (205 [9.2%] with confirmed syphilis and 66 [2.9%] with probable syphilis) in order to determine the effect of syphilis co-infection on HIV disease progression. In multivariate models censored at highly active antiretroviral therapy (HAART) initiation or last visit, adjusting for CD4 count, age, race, gender, and hepatitis B and C status, syphilis (confirmed + probable) was not associated with increased hazard of AIDS or death (hazard ratio 0.99, 95% CI 0.73–1.33). Treating HAART as a time-varying covariate or limiting the analysis to only confirmed syphilis cases did not significantly alter the results. Despite transient changes in CD4 counts and viral loads, syphilis does not appear to affect HIV disease progression.