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OBJECTIVE: The multiple risk factors for major depression are interrelated through poorly understood developmental pathways. In 2002, the authors presented a developmental model for major depression in women. Based on similar methods, they here present an analogous model for men. METHOD: Using data from 2,935 adult male twins, interviewed twice over a 2–4-year period, the authors constructed, by means of structural equation modeling, an integrated etiologic model for major depression that predicts depressive episodes over 1 year from 18 risk factors conceptualized as five developmental “tiers” reflecting childhood, early adolescence, late adolescence, adulthood, and the last year. RESULTS: The best-fitting model, including six correlations and 76 paths, provided a good fit to the data, explaining 49% of the variance in the liability to depressive episodes. The overall results, similar to those seen in women, suggest that the development of major depression results from the action and interaction of three broad pathways of internalizing symptoms, externalizing symptoms, and adversity. Childhood parental loss and low self-esteem were more potent variables in the model in men than in women. Genetic risks for major depression had a broader spectrum of action in men than in women. The pathway to major depression through externalizing symptoms was not more prominent in men than in women. CONCLUSIONS: Major depression in men, as in women, is an etiologically complex disorder influenced by risk factors from multiple domains that act in developmental time. The similarities in etiologic pathways to major depression for men and women outweigh the modest differences.