The polymorphic arylamine N-acetyltransferases (NAT1 and NAT2) have been implicated in increased susceptibility to certain malignancies. We analyzed genetic polymorphisms in both the NAT1 and NAT2 genes among 140 gastric adenocarcinoma patients, 103 colorectal adenocarcinoma patients and 122 healthy controls from Japan. The frequency of the specific genotype NAT1*10 allele, which contains a variant polyadenylation signal, was higher among all gastric adenocarcinoma cases, but this increase did not reach statistical significance. After grouping according to tumor differentiation of gastric adenocarcinoma patients, NAT1 polymorphism was a risk factor among the well-differentiated type of tumors (OR โซุโฌ 3.03, 95% CI 1.08-8.46). Stratifying by smoking status, we found that the OR for heavy smokers with the NAT1*10 allele was 2.97 (95% CI 1.23-7.14). When the combined risk of NAT1*10 allele from smoking and tumor differentiation was calculated, we found that the risk of the NAT1*10 allele with heavy smoking was increased among the well -differentiated type of gastric adenocarcinoma (OR โซุโฌ 4.24, 95% CI 0.87-20.6). The NAT1*10 genotype was not a significant risk factor in colorectal adenocarcinoma. No statistically significant differences were observed in the frequency of NAT2 rapid acetylation genotype in gastric (91.4%) or colorectal (95.2%) adenocarcinoma patients when compared with the control population (94.3%). Our results suggest the NAT1*10 allele may be an important genetic determinant of the welldifferentiated type of gastric adenocarcinoma, which may be induced by smoking. Int.