The aim of this study was to investigate the association of environmental factors (dietary folate, methionine and drinking status) and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene, as well as the combination of these factors, with the risk of colon cancer and rectal cancer. A case-control study of 53 colon cancer patients, 73 rectal cancer patients and 343 healthy controls was conducted. Genotypes of C677T and A1298C polymorphisms were analyzed by PCR-RFLP. The dietary folate and methionine intakes were assessed using food-frequency questionnaires and food consumption tables. Unconditional logistic regression was applied to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs). The frequency of MTHFR 677T and 1298C alleles in healthy population were 39.4 and 17.2%, respectively. After adjustment for specific variants, the MTHFR 677TT genotype showed a significantly reduced risk of colon cancer compared with the wild type (OR=0.22, 95% CI: 0.50-0.98), and 1298C allele-carrier showed an inverse association with the risk of rectal cancer compared to the wild type (OR=0.52, 95% CI: 0.28-0.98). Adequate intake of folate was a protective factor from colon cancer (OR=0.32, 95% CI: 0.12-0.88) and MTHFR C677T polymorphism showed a statistically significant effect (OR=0.25, 95% CI: 0.06-0.93), reducing the risk of colon cancer in groups that have an intake of folate exceeding 115.64ng per 1000kcal per day. This study suggests that MTHFR C677T and A1298C polymorphisms are associated with the reduced risk of colon and rectal cancers, respectively. Adequate folate intake shows an inverse association with the risk of colon cancer. There is a significant interaction between MTHFR C677T polymorphism and folate intake in reducing the risk of colon cancer.