Importance Early onset major depressive disorder (MDD) is common in those at high familial-risk of depression and is associated with particularly poor long-term mental health, social and educational outcomes. Objective To examine the developmental pathways that lead to first episode adolescent-onset MDD (incident cases) in those at high familial risk. We postulated a theoretically-informed model that enabled the simultaneous testing of different pathways to incident adolescent-onset MDD. These pathways were composed of contributions from familial/genetic and social risk factors as well as effects via specific clinical antecedents. Design Four year longitudinal study of offspring of depressed parents. Setting General community Participants 337 families where the index parent (315 mothers and 22 fathers) had experienced at least two episodes of MDD (recruited through primary care) and, at baseline, there was a biologically related child in the age range 9-17 years living with the index parent (197 girls and 140 boys, mean age = 12.4 years). Offspring with MDD prior to the study or at baseline (27), or with an episode of MDD that had remitted by follow-up (4) and missing baseline MDD data (2) were excluded. 92% of families completed the follow-up. Main outcome measure Primary outcome: new-onset MDD; Secondary outcome: total DSM-IV MDD symptom score. Results Fear/anxiety (β=.38, p.1) and disruptive behavior (β= -.08, p>.1) were not. Results were similar for DSM-IV symptom count at follow-up. All the measured familial/genetic and social risk indicators directly influenced risk for new-onset MDD rather than indirectly through acting on dimensional clinical antecedents. Conclusions and relevance There are multiple pathways to first-onset adolescent depression in those at familial risk. Anxiety and irritability may be additional clinical phenomena to be included as targets in primary preventive interventions focusing on the child. As well as targeting clinical phenomena in parents and children, depression prevention methods in high-risk groups may need to take into consideration social risks such as poverty and psychosocial adversity.