The relationship between the G-protein beta3 subunit variant C825T and risk of hypertension was examined in a prospective cohort study of Japanese workers. This study included observations over a 5-year period from 1997 to 2002 on 878 males and 692 females who were normotensive at entry. Hypertension was defined as systolic blood pressure > or =140 mmHg and/or diastolic blood pressure > or =90 mmHg, or taking antihypertensive medication. Pooled logistic regression analyses were performed using C825T genotype, age, body mass index, lifestyle, and the result of blood chemistries as the covariates. Multivariate pooled logistic regression analysis showed the risk of hypertension was 2.31 times higher in females with the TT genotype than in females with the CC genotype (95% confidence interval: 1.07-4.96), after adjustment for the effects of other potential covariates. In contrast, no significant risk of hypertension was observed with the TT genotype in male subjects. This study indicates that the 825T allele is an independent risk factor for hypertension in Japanese females, and suggests that this polymorphism may be a beneficial prognostic marker for hypertension in the general Japanese female population.