Objective Adolescents with bipolar disorder (BD) are more likely to develop substance use disorders (SUDs) than adolescents without psychiatric disorders; however, to our knowledge, specific risk factors underlying this relationship have not been prospectively examined. The purpose of this study was to identify predictors of developing SUDs after a first manic episode. Method Participants aged 12 to 20 years and hospitalized with their first manic episode associated with bipolar I disorder (BP-I) were recruited as part of the University of Cincinnati First-Episode Mania Study and prospectively evaluated for patterns of substance use. Follow-up ranged between 17 and 283 weeks (mean = 113 weeks, SD = 71.9 weeks). Demographic and clinical variables were compared between adolescents with and without SUDs. Results Of the 103 adolescents with BD, 49 (48%) either had a SUD at baseline or developed one during follow-up. Of the 71 participants who did not have a SUD at study entry, 17 (24%) developed one during follow-up (median = 40 weeks). Later onset of BD, manic (versus mixed) mood episode, and comorbid disruptive behavior disorders were associated with an increased risk of developing a SUD in univariate analyses. Adolescents treated with psychostimulant treatment before their first manic episode were significantly less likely to develop a SUD independent of attention-deficit/hyperactivity disorder (ADHD) diagnosis. Comorbid posttraumatic stress disorder (PTSD) and psychotic symptoms were the strongest predictors of SUD development. Conclusion Our results confirm high rates of SUD in adolescents with BD. In addition, our findings identify potential risk factors associated with SUDs in adolescents with BD. These data are preliminary in nature and should be explored further in future studies.