CONTEXT: Although an association between mood disorders and substance use disorders has been well established, there is a lack of long-term prospective data on the order of onset and subtypes of mood disorders associated with specific substances and their progression. OBJECTIVE: To estimate the respective risks posed by subtypes of mood disorders or bipolar spectrum conditions for the subsequent development of substance use disorders. DESIGN: Six waves of direct diagnostic interviews were administered to a sample of young adults during a 20-year period. Mood disorders and syndromes assessed at each interview were used to predict the cumulative incidences of substance use disorders at subsequent interview waves. PARTICIPANTS: We followed up 591 individuals (292 men and 299 women) who were selected at study enrollment from a representative sample of young adults in Zurich, Switzerland. MAIN OUTCOME MEASURES: Structured Diagnostic Interview for Psychopathologic and Somatic Syndromes, a semistructured clinical interview that collected data on the spectrum of expression of mood disorders and substance use and disorders for DSM-III-R and DSM-IV criteria. RESULTS: Individuals having manic symptoms were at significantly greater risk for the later onset of alcohol abuse/dependence, cannabis use and abuse/dependence, and benzodiazepine use and abuse/dependence. Bipolar II disorder predicted both alcohol abuse/dependence and benzodiazepine use and abuse/dependence. In contrast, major depression was predictive only of later benzodiazepine abuse/dependence. CONCLUSIONS: In comparison with major depression, bipolar II disorder was associated with the development of alcohol and benzodiazepine use and disorders. There was less specificity of manic symptoms that tended to predict all levels of the substances investigated herein. The different patterns of association between mood disorders and substance use trajectories have important implications for prevention and provide lacking information about underlying mechanisms.