Because cytochrome P-450 2E1 (CYP2E1) is involved in metabolic activation of environmental chemical carcinogens, gene polymorphisms that alter its functions may be associated with cancer susceptibility. However, previous studies have revealed disconcordant results with regard to cancer risk. To investigate gene-environment interactions with the RsaI polymorphism of CYP2E1 in terms of risk of esophageal and stomach cancers, we conducted a case-control study with 93 esophageal and 98 stomach cancer cases and 196 population-based controls in a high-endemic area for these cancers of China. We assayed genomic DNA samples for RFLPs in the CYP2E1 by PCR amplification, followed by digestion with RsaI, and collected information on environmental factors by a questionnaire approach. Odds ratios were estimated with an unconditional logistic model, after adjustment for potential confounding factors. The proportional distribution of the homozygous common RsaI alleles did not differ between cancer cases of the esophagus (59.1%) and stomach (59.2%), and controls (61.7%). However, we found a significant positive interaction between the heterozygous and homozygous RsaI rare alleles and ever-smoking in the odds ratio for stomach cancer (P = 0.015). The interaction between the gene polymorphism and dietary factors, such as garlic consumption, was not observed in both cancer cases. These results suggest that gene-environment interactions between the CYP2E1 polymorphism and smoking may have the potential to alter the susceptibility for cancer development in the stomach.