Single nucleotide polymorphisms (SNPs) have potential as markers for identifying genes responsible for common diseases and for personalized medicine. To investigate the association between polymorphisms and gastrointestinal (gastric and colorectal) cancer, we performed a hospital-based case-control study in Japan.We screened a total of 214 SNPs in 44 candidate genes by using a mass spectrometry-based technique (MassARRAY; Sequenom, Inc., San Diego, CA). In this study, 153 patients and 302 controls for gastric cancer and 121 patients and 245 controls for colorectal cancer were matched with regard to age, sex, and residential area. Genes were selected based on their possible interactions with the environment and lifestyle, and the candidate genes constitute those encoding xenobiotic metabolism enzymes, DNA repair enzymes, and other stress-related proteins. Each polymorphism was tested in controls to ensure its fit with Hardy-Weinberg equilibrium. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by conditional logistic regression analysis to estimate the association between genetic polymorphisms and the risk of gastric and colorectal cancers.Twenty-one SNPs in nine genes were associated with the risk of gastric cancer (P < 0.05) and 15 SNPs in nine genes were associated with the risk of colorectal cancer (P < 0.05).The findings of the present study will be the basis for future large-scale association studies of gene-environment factors using the candidate gene approach for the Japanese population.