OBJECTIVE: Depressive episodes among alcohol-dependent men and women are heterogeneous in causation and clinical course. This study tested three hypotheses regarding the rates and clinical characteristics of two potential subtypes of these affective states: those that appear to be substance-induced mood disorders and those that are independent major depressive episodes. METHOD: Semistructured, detailed interviews were administered to 2,945 alcohol-dependent subjects as part of the Collaborative Study on the Genetics of Alcoholism. With the use of a time line method for determining the type of mood disorder among probands, relatives, and comparison subjects, individuals with histories of the two types of mood disorders were compared. RESULTS: Major depressive episodes with an onset before the development of alcohol dependence or during a subsequent long abstinence period (i.e., independent depressions) were observed in 15.2% of the alcoholics, while 26.4% reported at least one substance-induced depressive episode. According to a logistic regression analysis, the subjects with independent (as compared to substance-induced) major depressive episodes were more likely to be married, Caucasian, and female, to have had experience with fewer drugs and less treatment for alcoholism, to have attempted suicide, and, on the basis of personal interviews with family members, to have a close relative with a major mood disorder. CONCLUSIONS: These results support the contention that it is possible to differentiate between what appear to be substance-induced and independent depressive episodes in alcoholics. Such differentiation might be important for establishing prognosis and optimal treatment.