Studies investigating the association between cytochrome P450 2E1 (CYP2E1) 5'-flanking region (PstI/RsaI) polymorphism and gastric cancer risk report conflicting results. The rationale for this meta-analysis was to determine whether CYP2E1*2 (c2) variant allele of CYP2E1 increases gastric cancer risk, especially by interacting with smoking, alcohol and other metabolic gene polymorphisms. Two investigators independently searched the Medline and Embase databases. A qualitative scoring of papers was applied to their evaluation. Authors of the identified papers were contacted to obtain data on the mentioned co-exposures. A measurement of the biological interaction among two putative risk factors was estimated by the attributable proportion (AP) due to interaction. We identified 13 case-control studies, which included 2066 gastric cancer cases and 2754 controls. Using the random effects model, we found no association between PstI/RsaI genotype and gastric cancer risk [odds ratio (OR) = 0.97 (95% confidence interval (CI): 0.79-1.18) for c2 allele carriers and OR = 1.36 (95% CI: 0.82-2.25) for c2 homozygotes compared with homozygotes wild-type]. When only high-quality scored studies were considered, a statistically significant increased risk appeared among Asians [OR = 1.50 (95% CI: 1.16-1.94) for c2 carriers and OR = 2.62 (95% CI: 1.23-5.57) for c2 homozygotes]. No interaction was detected between CYP2E1-smoking/alcohol (AP = 0), while an AP of 60% appeared for individuals both c2 homozygotes and glutathione S-transferase M1 (GSTM1) null compared with both homozygotes wild-type. This meta-analysis suggests that the CYP2E1 PstI/RsaI polymorphism may be a risk factor for gastric cancer in Asians, and that a synergic relation among GSTM1 and CYP2E1 may account for a proportion of gastric cancer cases.