The T allele of the C825T polymorphism in the G-protein beta(3) subunit gene (GNB3) is related to the increase of signal transduction by the G-protein. G-proteins are intermediary paths in signal transduction from receptors involved in mood regulation and substance dependence. We studied the C825T polymorphism in individuals with (i) alcohol and nicotine dependence (n = 109), (ii) nicotine dependence only (n = 117) and (iii) non-dependent controls (n = 108). We also tested for possible associations with psychiatric comorbidities among alcohol-dependent individuals. No differences were detected for allele and genotype frequencies in individuals with or without dependencies. Alcohol-dependent individuals with the heterozygous genotype presented more frequently major depressive disorder (chi(2) = 12.34; p = 0.002). These findings, taken together with other studies suggesting an influence of the C825T polymorphism in major depressive disorder, support the hypothesis of the involvement of G-proteins in mood regulation.