Objective: To identify childhood psychopathological features that predict the onset of adolescent Bipolar (BD) versus Unipolar Major Depressive Disorder (UD) during adolescence. Method: We analyzed clinical data from 495 juveniles diagnosed with DSM-5 UD (n = 359), and BD (n = 136), using bivariate analysis and multivariate logistic regression model. Results: BD subjects exhibited earlier onset of any psychiatric feature compared to UD. Antecedents associated with later BD were: oppositional defiant > specific phobias > ADHD > obsessive compulsive (OCD). Antecedents selectively associated with later UD were: social anxiety and separation anxiety. Factors significantly and independently associated with later BD diagnosis were: [a] emotional dysregulation at onset of the mood disorder; [b] first depressive episode with mixed features; [c] antecedent ADHD; [d] antecedent OCD, and [e] antecedent oppositional-defiance. Conclusion: Identifying developmental differences in BD and UD symptoms can aid clinicians in early identification and treatment planning for bipolar disorder in youth.