Sulfotransferases (SULT) catalyze both the bioactivation and detoxification of a wide range of promutagens and procarcinogens. SULT1A1 appears to be an important phenol SULT because of its abundance and distribution in many tissues and wide substrate specificity. The SULT1A1 gene possesses a G-->A polymorphism that results in an Arg to His amino acid substitution, and the His(213) allele has been shown to have low activity and low thermal stability. Because of its functional role and published data showing the influence of Arg213His polymorphism on the risk of some cancers, we hypothesized that the His(213) allele of the SULT1A1 gene may modify bladder cancer risk. To test this hypothesis, we determined the SULT1A1 Arg213His genotypes in 384 incident bladder cancer patients and 386 healthy frequency-matched controls. A comprehensive epidemiologic interview was conducted on all participants to collect personal information, such as demographics and smoking status. The Arg/His and His/His genotypes were more common in the controls than the cases (P=0.035), resulting in a His(213) allele frequency of 35.0% in controls and 28.8% in cases. When individuals with the His(213) allele genotypes (Arg/His+His/His) were combined and compared to individuals with the Arg/Arg genotype, we observed a statistically significant reduced risk of bladder cancer (OR=0.72; 95% CI 0.54-0.97). When we examined the data by gender, there was a statistically significant reduced risk of bladder cancer only in women (OR=0.42; 95% CI 0.23-0.78) and not in men (OR=0.84; 95% CI 0.60-1.19) with the His(213) genotypes. In addition, there was a reduced bladder cancer risk in never smokers (OR=0.59; 95% CI 0.36-0.98) with the His(213) allele genotypes, but not in former (OR=0.82; 95% CI 0.54-1.25) or current smokers (OR=0.68; 95% CI 0.29-1.58). The His(213) allele genotypes also appeared to provide some protective benefit for current and former smokers, as compared to those with the Arg/Arg genotype. In conclusion, this study provides epidemiologic evidence of a reduced bladder cancer risk associated with the SULT1A1 His(213) polymorphism. Further studies are warranted to elucidate the function of this SULT1A1 polymorphism with regard to organ specificity, gene-environment interactions, and the gender-related difference we observed.