A hospital-based case-control study was conducted to evaluate the significance of methionine and folate related polymorphisms, with 72 colon and 70 rectal cancer cases and 241 non-cancer controls. The polymorphisms examined were in the genes for methionine synthase reductase (MTRR A66G), methionine synthase (MTR A2756G) and methylenetetrahydrofolate reductase (MTHFR C677T and A1298C). An unconditional logistic regression model was applied for estimating the odds ratios (ORs) and 95% confidence intervals (CIs). The age-sex adjusted OR for the MTRR GG genotype as compared with the AA and AG genotypes was 2.77 (95% CI: 1.39-5.53, p = 0.004), whereas adjusted ORs for other polymorphisms were not statistically significant. When the ORs for environment factors (smoking, alcohol consumption, body-mass-index, and physical exercise) were calculated according to each polymorphism, no substantial difference was observed except with the MTRR polymorphism. The ORs for the MTRR GG genotype seemed to be modified by the extent of environmental exposure. In conclusion, the present study showed that the GG genotype of MTRR A66G is a risk factor for colorectal cancer in Japanese, while MTHFR and MTR polymorphisms are not. The conclusions, however, need further evaluation in terms of micronutrient status and additional confirmatory studies are required with datasets for various ethnic groups.