Objective-To examine the association between onset of substance use and risk factors related to suicide.Method-1,252 adolescents in two urban school districts completed surveys as part of a large, randomized controlled prevention effectiveness trial. Risk factors measured included depressive symptoms, suicide ideation, suicide ideation specifically with alcohol and/or drug use, endorsement of suicide as a personal option, and suicide attempt.Results-In our final multivariate models that controlled for current substance use and demographic characteristics, we found that earlier onset of hard drug use among boys was associated with all five suicide risk factors. In comparison, among girls, earlier onset of regular cigarette smoking, getting drunk, and hard drug use was associated with some of suicide risk factors.Conclusions-The findings confirm the importance of screening for substance use in early adolescence. The association between early substance use and suicide risk factors differed by gender; both research and intervention efforts need to incorporate gender differences.