OBJECTIVE: This study used an adoption study design to separate genetic from environmental factors in the etiology of depression spectrum disease, a type of major depression characterized by families in which male relatives are alcoholic and females are depressed. The genetic etiology hypothesis of depression spectrum disease proposes that an alcoholic genetic diathesis predisposes to depression in females but alcoholism, not depression, in males. METHOD: The study examined 197 adult offspring (95 male and 102 female) of alcoholic biological parents and used logistic regression models to determine the contribution to major depression in male and female adoptees that could be explained by the genetic alcoholic diathesis combined with an environmental factor that was characterized by psychiatrically or behaviorally disturbed adoptive parents. RESULTS: Major depression in females was predicted by an alcoholic diathesis only when combined with the disturbed adoptive parent variable. The same regression model failed to predict depression in males. Other possible environmental confounding factors contributing to an increased chance of depression were found in females: fetal alcohol exposure, age at the time of adoption, and a family with an adopted sibling who had a psychiatric problem. These variables did not diminish the significance of the prediction of depression with the alcohol genetic diathesis and disturbed parent model. CONCLUSIONS: The results show that a genetic factor is present for which alcoholism is at least a marker, and which exerts its effect in women as a gene-environment interaction leading to major depression. This finding suggests that an important etiologic factor in depression spectrum disease is gene-environment interaction.