Several, but not all, studies have reported that a variant genotype of the polymorphism (C677T) of 5,10-methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, is associated with a decreased risk of colorectal cancer. A case-control study was conducted to investigate the association of MTHFR polymorphism and heavy alcohol intake to colon and rectal cancer in Korean. Cases were a consecutive series of patients with histologically confirmed, incident colorectal cancer who were admitted to two university hospitals in Seoul, Korea between 1998 and 2000, and controls were selected at the same hospitals. A total of 243 cases (colon 111, rectum 132) and 225 controls were enrolled. While the genotype of MTHFR was not associated with the overall risk of colorectal cancer, increased colon cancer risk was found to be associated with the CT and TT genotypes combined (multivariate odds ratio [OR] 2.01, 95% confidence interval [CI] 1.14-3.53) compared with the wild type. The risk of rectal cancer was found to be, though statistically non-significant, lower in those with the CT and TT genotypes combined (multivariate OR 0.67, 95% CI: 0.43-1.07). Those consuming two or more drinks per day (30 g+/day) had nearly twice the colorectal cancer risk (multivariate OR 1.94, 95% CI 1.03-3.68) of light or non-drinkers (<5 g/day). The present study did not find a reduced risk of colorectal or rectal cancer among those with a variant genotype of the MTHFR polymorphism, but observed rather an increased risk of colon cancer, suggesting that the effects of the MTHFR genotype may differ in populations with different levels of folate intake.