The aim of the present study is to test for possible associations between the C-1291G polymorphism in the alpha2A-adrenergic receptor gene (ADRA2A) with tobacco smoking and alcohol dependence. The genotype and allele frequencies were compared in three groups of European-derived Brazilian males: individuals with co-occurrence of tobacco smoking and alcohol dependence (N = 110), with tobacco smoking (N = 121) and controls (N = 114). The frequency of the G allele was higher in the group with both conditions, intermediate among subjects with smoking, and lower among controls (chi(2) = 8.00; p = 0.02). The chi(2) partitioning did not reveal significant differences between the sample with the two conditions and the sample of smokers (chi(2) = 0.82; p = 0.36). Combining both groups, the difference to the non-smoking controls is higher than the one observed in the three-groups analysis (chi(2) = 7.18; p = 0.007). The results suggest a role for the ADRA2A C-1291G polymorphism, notably the G allele, in the predisposition to tobacco smoking. The influence of the ADRA2A gene in nicotine and other substance dependencies should be more extensively assessed in future studies.