Young men in South Africa experience several adverse socio-structural and psychosocial factors that may contribute HIV risk behaviors. This study applied a syndemic framework to explore whether these syndemic factors are interconnected and work in synergy to increase HIV risk behaviors. Five syndemic factors were assessed including: binge drinking, polydrug use, depressive symptoms, violence and food insecurity on two HIV risk behaviors: multiple sex partners and transactional sex. Participants were (N = 1233) young men aged 18-29 years from a township in Cape Town, South Africa. Bivariate logistic regression analysis demonstrated that many of the syndemic factors were related to one another. Pairwise interactions (on an additive scale) among the syndemic factors revealed significant positive interactions between binge drinking and violence on greater odds of reporting multiple sex partners (aOR = 5.10, 95% CI 3.10, 8.29; p = < .001) compared to reporting neither factor. Also, food insecurity and violence (aOR = 2.89, 95% CI 1.63, 5.11; p = < .001) as well as food insecurity and polydrug use (aOR = 2.73, 95% CI 1.54, 4.84; p = < .001) were significantly associated with greater odds of transactional sex compared to reporting neither factor. Our findings highlight a synergistic relationship between some adverse socio-structural and psychosocial factors on HIV risk behaviors. HIV prevention programs that address multiple syndemic factors simultaneously may achieve greater impact on HIV risk reduction.