This study examined HIV transmission risk behavior among 63 patients with bipolar disorder (BD), major depressive disorder, and no mood disorder; half had substance use disorders (SUDs). Patients with BD were more likely than others to report unprotected intercourse with HIV-negative partners and <95 % adherence to antiretroviral medications. In multivariate models, BD and SUD were independent predictors of both risk behaviors. Participants with poorer medication adherence were more likely to have detectable HIV viral loads and unprotected intercourse with HIV-negative partners. Patients with BD deserve careful evaluation and HIV prevention services to reduce HIV transmission risk behaviors.