Association studies of the TaqI A allele of the dopamine receptor D2 (DRD2) gene with alcohol dependence have produced conflicting findings. Although a wide series of clinical features have been considered in the different association studies performed, very few studies specifically analyzed the role of gender. We compared the TaqI A polymorphisms of the DRD2 gene in 120 French Caucasian alcohol-dependent inpatients (62 males and 58 females) and 107 healthy ethnically matched controls (66 males and 41 females). We observed that 55% of alcohol-dependent males have at least one A1 allele, a prevalence that is significantly above that observed in the control males (38%). On the contrary, no differences were found in females between the alcohol-dependent inpatients and controls for the A1 allele prevalence. In our sample, this male-specific association was not explained by gender specificities of alcohol dependence, such as age at onset and severity measures (mean numbers of social, somatic, and withdrawal complications). On the other hand, alcohol-dependent women with the A1 allele reported more frequently a major depressive disorder (70% vs. 40%, P = 0.03). We thus replicated the allelic association of the A1 allele of the DRD2 gene with alcohol dependence, but showed a male-limited effect of this "vulnerability allele." Recent evidence for gender difference in dopamine D2-like receptor levels and affinity may explain this discrepancy.