Compared with men who have sex with men only (MSMO), men who have sex with men and women (MSMW) consistently report higher rates of two HIV risk behaviors: transactional sex (TS) and concurrent substance use and sex (CSS). Within MSMW, little is known about how synergistic epidemics ("syndemics") affect TS and CSS. Using a sample of substance-using MSM (n = 515) in South Florida, we compared TS and CSS among MSMO and MSMW; examined whether, within MSMW (n = 86), TS and CSS predict unprotected anal intercourse with partners of serodiscordant/unknown HIV status (SU-UAI); and tested whether syndemics predict TS and CSS. MSMW reported higher rates of engaging in both TS and CSS (AOR = 1.7; 95 % CI 1.0-3.0). Within MSMW, engagement in both TS and CSS predicted SU-UAI (AOR = 3.3; 95 % CI 1.2-9.6); and syndemics predicted TS and CSS involvement (p < 0.01). Substance-using MSMW may benefit from interventions targeting TS, CSS, and background syndemics.