Increasing evidence suggests that variants of common and low-penetrance genes are involved in pancreatic cancer (PC) carcinogenesis. We undertook a meta-analysis of published studies to assess evidence regarding the risk associated with these genes. Medline, Web of Science, ProQuest, Google Scholar, and international conference proceedings were searched and citations in relevant primary and review articles were collected. The studies that we considered eligible included all reports that investigated an association between genetic polymorphisms and PC. We identified 23 studies that evaluated the risk effects on PC of common alleles for 13 gene polymorphisms. A significant association was recognized between ALDH 2*1*2 polymorphisms and PC [odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.07-1.75, P = 0.01] based on only two studies. Although the overall results for MTHFR T677T are negative, sensitivity analysis stratified by ethnic background showed a significant association between Caucasian and MTHFR T677T polymorphisms and PC (OR = 1.66, 95% CI = 1.10-2.52, P = 0.02). The risk for PC was higher in individuals with MTHFR C677T or TT polymorphisms and a smoking habit (OR = 2.52, 95% CI = 1.05-6.09, P = 0.04). These findings lead us to support the hypothesis that MTHFR T677T and ALDH 2*1*2 polymorphisms may play a carcinogenetic role in PC and represent the candidates for low-penetrance susceptibility alleles identified to date. Although their genetic risks are modest, the high frequency in the population shows that they may have a considerable impact on the incidence of PC. Definite conclusions will be contingent on studies with a larger sample size that determine the risk estimates associated with other variants, gene-gene, and gene-environment interactions.