This study examined the interaction of depressive symptoms and drug use on HIV/STI risk among sexual minority young adults. Analyses tested the interactive effect of depressive symptoms and drug use on unprotected sex. Among drug users, more depressive symptoms were associated with higher rates of unprotected sex with a male partner (for both male and female participants) but this was non-significant for non-users. Interventions with these groups should incorporate content on depression and drug use to reduce HIV/STI risk. Prevention efforts also should not neglect the vulnerability of young women that have sex with women and/or identify as non-heterosexual.