Background: The objective of this study was to examine the epidemiology of syphilis among high-risk socially marginalized populations in urban, coastal Peru, to quantify the prevalence of recent syphilis infection and identify risk factors. Methods: Survey data and serologic specimens were collected from a population-based sample of 3 populations: men who have sex with only men (MSOM), socially marginalized heterosexual men, and socially marginalized women. Syphilis prevalence was determined for each population, and multivariate analysis was used to analyze risk factors for recent syphilis infection among the MSOM and among the socially marginalized men. Results: The prevalence of recent syphilis infection was 10.5% among the MSOM, 1.5% among the socially marginalized men, and 2.0% among the women. Among both MSOM and the socially marginalized men, recent syphilis infection was significantly associated with Herpes simplex virus Type 2 infection (prevalence ratio = 1.96; 95% confidence interval, 1.03-3.74, and PR = 3.72; 95% CI, 2.12-6.53, respectively). Recent syphilis infection was also significantly associated with HIV infection among the socially marginalized men (PR = 11.13; 95% CI, 4.50-27.51) and with the number of sexually active years among the MSOM (PR = 1.05, 95% CI, 1.01-1.10). Conclusions: All 3 groups included in this study exhibited a high prevalence of recent syphilis infection, with recent infection being most prevalent among the MSOM. These findings demonstrate the need for more effective syphilis control services among those populations, to decrease syphilis-associated morbidity, transmission of syphilis, and the potential transmission of HIV. © Copyright 2010 American Sexually Transmitted Diseases Association.