Recurrent, early-onset, major depressive disorder (RE-MDD) is a strongly familial condition whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. Sixteen of the 19 candidate susceptibility loci identified by a recent genome survey revealed allelic associations with RE-MDD in men or women, but not in both sexes. The association of D2S2944 alleles and genotypes with RE-MDD and related disorders was evaluated using a case-control study design employing 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. The results of the case-control study were subsequently evaluated in a sample of 81 families ascertained through probands with RE-MDD using the transmission/disequilibrium test. The frequency of the D2S2944 124-bp allele among women with RE-MDD was approximately three times that for female controls (P = 0.0003). Women who carried the D2S2944 124-bp allele revealed a significantly elevated risk of developing RE-MDD, as indicated by an odds ratio of 4.5 compared to female controls (P<0.001). In contrast, men with RE-MDD did not have an increased frequency of this allele compared to male controls, and men who were carriers did not exhibit an increased risk of developing RE-MDD or related disorders. Our findings also suggest that the D2S2944 124-bp allele increases the risk of alcohol and other substance use disorders among women with RE-MDD. The transmission/disequilibrium test provided confirmatory evidence of these sex-specific findings within families. The results of this study confirm the existence of sex-specific susceptibility loci for RE-MDD, and suggest that there may be important differences in the molecular pathophysiology of RE-MDD in men and women. Alternatively, our findings may reflect the existence of sex-specific differences in the molecular mechanisms that determine resilience to endogenous or environmental depressogenic stimuli. The identification and characterization of the D2S2944 susceptibility locus for RE-MDD and related substance use disorders is likely to provide important new insights into the clinical biology, treatment, and prevention of these disorders.