OBJECTIVE: Gender differences exist in the prevalence and psychiatric comorbidity of major depressive disorder (MDD). This study investigates whether familiality of MDD contributes to observed gender differences in comorbidity. METHOD: Familial (f-MDD) and non-familial (nf-MDD) MDD cases from a population sample were assessed for comorbid dysthymia, anxiety disorders and alcohol-related disorders using the Composite International Diagnostic Interview (CIDI). Logistic regression analyses were performed to examine the effect of f-MDD on gender differences in comorbidity, adjusted for confounders. RESULTS: Women with f-MDD reported significantly more comorbid dysthymia and generalized anxiety disorder (GAD) than their male counterparts; women with nf-MDD reported significantly more comorbid simple phobias and agoraphobia than their male counterparts. Gender differences in comorbid panic disorder and alcohol-related disorders occurred independently of the familial load. Adjustment for age of onset, severity and recurrence of MDD did not change these results. CONCLUSION: Models to explain comorbidity patterns of MDD differ by gender. Familiality of MDD should be taken into account.