BackgroundConcurrent psychosocial problems may synergistically increase the risk of HIV infection (syndemics), representing a challenge for prevention. We aimed to evaluate the prevalence and associated factors of syndemics among men who have sex with men (MSM) and transgender women (TGW) enrolled in the Brazilian pre-exposure prophylaxis demonstration study (PrEP Brasil Study). MethodsSecondary cross-sectional analysis of the PrEP Brasil Study was performed. Of 450 HIV-seronegative MSM/TGW enrolled in the PrEP Brasil Study– conducted at Rio de Janeiro and São Paulo, Brazil– 421 participants with complete data were included in the present analysis. Syndemics was defined as occurrence of ≥2 of the following conditions: polysubstance (≥2) use, binge drinking, positive depression screen, compulsive sexual behavior, and intimate partner violence (IPV). ResultsThe prevalence of recent polysubstance use was 22.8%, binge drinking 51.1%, positive depression screening 5.2%, compulsive sexual behavior 7.1%, and IPV 7.3%. Syndemics prevalence was 24.2%, and associated factors were younger age (adjusted Odds Ratio (aOR) 0.95, 95% Confidence Interval (95% CI) 0.92–0.98 per year increase), TGW vs. MSM (aOR 3.09, 95% CI: 1.2–8.0), some college education or more vs. less than college (aOR 2.49, 95% CI: 1.31–4.75), and multiple male sexual partners in prior 3 months (aOR 1.69, 95% CI: 0.92–3.14). ConclusionGiven the high prevalence of syndemics, particularly of polysubstance use and binge drinking, PrEP delivery offers an opportunity to diagnose and intervene in mental and social well-being.