BACKGROUND: Concomitant syphilis and human immunodeficiency virus (HIV) infection is increasingly frequent in industrialized countries. METHODS: From a large hospital cohort of HIV-infected patients followed up in the Paris area between 1998 and 2006, we examined the effect of early syphilis on plasma HIV-1 RNA levels and CD4 cell counts. We compared 282 HIV-1-infected men diagnosed as having incident primary or secondary syphilis with 1233 syphilis-free men matched for age (±5 years), sexual orientation, participating center, length of follow-up (±6 months), and immunologic and virologic status before the date of syphilis diagnosis (index date). Increase in viral load (VL) (plasma HIV-1 RNA) of at least 0.5 log or a rise to greater than 500 copies/mL in patients with previously controlled VL during the 6 months after the index date was analyzed, as were CD4 cell count variations and CD4 slope after the index date. RESULTS: During the 6 months after the index date, VL increase was observed in 77 men with syphilis (27.3%) and in 205 syphilis-free men (16.6%) (adjusted odds ratio [aOR], 1.87; 95% CI, 1.40-2.49). Even in men with a VL of less than 500 copies/mL undergoing antiretroviral therapy, syphilis was associated with a higher risk of VL increase (aOR, 1.52; 95% CI, 1.02-2.26). The CD4 cell count decreased significantly (mean, -28/μL) compared with the syphilis-free group during the syphilis episode (P = .001) but returned to previous levels thereafter. CONCLUSIONS: In HIV-infected men, syphilis was associated with a slight and transient decrease in the CD4 cell count and with an increase in VL, which implies that syphilis may increase the risk of HIV transmission, even in patients receiving antiretroviral therapy and with a VL of less than 500 copies/mL.