The persistent HIV epidemic among men who have sex with men (MSM) suggests that continued research on factors associated with risky sexual behavior is necessary. Drawing on prior literature, the role of depression and substance use in HIV risk is also inconclusive. Generalizability of past findings may also be limited to the extent that research has not employed probability samples. Here we report on one of the few probability samples of MSM to examine the role of depressive symptoms and substance use on risky sexual behavior (RSB). Multinomial logistic regression analysis suggested that depression and substance use are independently linked to our risk measure, such that those reporting high levels of depressive symptoms or substance use were more likely to report both unprotected receptive anal intercourse and unprotected insertive anal intercourse, and sex with a risky partner. Implications for prevention and treatment are discussed. (C) 2012 Elsevier Ltd. All rights reserved.