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OBJECTIVE: Substantial evidence supports the heritability of lifetime major depression. Less clear is whether genetic influences in major depression are more important in women than in men and whether genetic risk factors are the same in the two sexes. It is not known whether genetic effects on major depression are constant across historical cohorts. METHOD: Lifetime major depression was assessed at personal interview by modified DSM-IV criteria in 42,161 twins, including 15,493 complete pairs, from the national Swedish Twin Registry. Twin models were evaluated by using the program Mx. RESULTS: Model fitting indicated that the heritability of liability to major depression was significantly higher in women (42%) than men (29%) and the genetic risk factors for major depression were moderately correlated in men and women. No significant differences were seen in the etiologic roles of genetic and environmental factors in major depression in three cohorts spanning birth years 1900–1958. CONCLUSIONS: In the largest sample to date, lifetime major depression was moderately heritable, with estimates similar to those in prior studies. In accord with some but not other previous investigations, this study suggests both that the heritability of major depression is higher in women than in men and that some genetic risk factors for major depression are sex-specific in their effect. No evidence was found for differences in the roles of genetic and environmental risk factors in major depression in birth cohorts spanning nearly six decades.