Tobacco smoke inhibits monoamine oxidase-B (MAO-B) activity in vitro and in vivo, suggesting that MAO-B inhibition is a possible contributing factor to tobacco smoke addiction. Thus, MAO-B is a possible candidate gene for predisposition to smoking. The TaqIB polymorphism for the Dopamine D2 Receptor gene (DRD2) has been previously associated with smoking status, although with some contradictory results. We investigated whether genetic variants of MAO-B intron 13 and DRD2 TaqIB polymorphism could be associated with smoking status among control subjects. There was no association of the intron 13 polymorphism itself with smoking status in either men or women. Similarly, no association with smoking status was observed for the TaqIB polymorphism of DRD2 itself. However, among men, there was an interaction between MAO-B intron 13 polymorphism and the DRD2 TaqIB polymorphisms, in which subjects carrying MAO-B allele A and genotype B12 of DRD2 were 2.50 times (95% CI=1.05-5.95) more likely to be ever-smokers than the pool of men carrying all other genotype combinations. These results demonstrate that particular combinations of genotypes for MAO-B and DRD2 genes are associated with significantly higher risk for smoking behavior in men, but not in women.