The etiology of alcohol dependence is a complex interaction of psychosocial and biologic factors. To study the impact of genetic factors that play an important role in an individual's vulnerability to alcohol abuse and dependence, we examined the genetic variations of the major neurotransmitter genes, including the dopamine D2 receptor (DRD2) TaqI A, B, and -141C insertion/deletion (Ins/Del) polymorphisms, the serotonin transporter-linked polymorphic region (5-HTTLPR), and the gamma-aminobutyric acid A (GABA(A)) receptor beta(3) subunit gene (GABRbeta3), for 130 Mexican-American alcoholic men and 251 nonalcoholic control subjects (105 men and 146 women). The genotype frequency for the DRD2 -141C Ins/Del allele was significantly different between alcoholic and control subjects (P=.007). The frequency of the 5-HTTLPR short (S) allele was significantly higher in alcoholic individuals (61.5%) than in nonalcoholic control subjects (52.8%; P=.021). When smokers were excluded from both control and alcoholic groups, the association between the DRD2 -141C Ins allele, as well as between the 5-HTTLPR S allele, and alcoholism became significant at both genotypic and allelic levels. No positive association was found between alcoholism and the DRD2 TaqI A or B, or the GABRbeta3, genotype. Our findings indicate that the DRD2 -141C Ins allele and the 5-HTTLPR S allele are genetic risk factors for alcoholism in Mexican-Americans, and that smoking modulates the association between genetic risk factors and alcoholism.