The beta-adrenoceptor (beta-AR) G(s) protein system has been shown to have important roles in the cardiovascular system. The gene encoding the alpha-subunit of G(s) proteins (GNAS1) is a candidate genetic determinant for hypertension. We studied the GNAS1 T393C polymorphism in >2000 Japanese individuals. chi(2) test showed a marginally significant difference in the frequencies of the alleles (P=0.036) and genotypes (P=0.094) between hypertensives and normotensives. Because hypertension is considered to be a complex disorder resulting from interactions between genetic and environmental factors, we further analyzed the T393C polymorphism, with consideration of interactions between the polymorphism and confounding factors in regression models. These analyses showed a significant interaction between the polymorphism and cigarette smoking in the pathogenesis of hypertension (P=0.0005). The interaction was reflected in a significant association of the polymorphism with hypertension in nonheavy smokers (P=0.0028; odds ratio, 1.52; 95% confidence interval, 1.16 to 2.00). A significant interaction between the polymorphism and aging in the pathogenesis of hypertension was also shown in nonheavy smokers. These findings may be helpful in conducting further molecular and biological studies on the relationship among cigarette smoking, the beta-AR-G(s) protein system, and hypertension.