This paper examines whether there is a relationship between a common mutation in the methylenetetrahydrofolate reductase gene, MTHFR*val, and the risk of colorectal cancer, with or without lymph node metastases. MTHFR genotypes were ascertained from peripheral leukocyte samples obtained from 200 colorectal patients, including TMN stages I-VI, and from 460 healthy, unrelated adults without colorectal cancer, who served as controls. The frequency of homozygosity for the MTHFR*val/*val genotype among the colorectal cancer patients was lower (14.0%) than among controls (16.1%). The latter finding results in an estimated MTHFR*val allele frequency of 0.41. The MTHFR*val allele (677C > T) reduces colorectal risk slightly [odds ratio (OR), 0.87]. However, there was a significantly higher incidence of metastatic lymph nodes per case in MTHFR*val/*val patients, when compared with MTHFR*ala/*ala controls (6.9 +/- 1.55 vs. 3.7 +/- 0.57, p = 0.003). These results suggest that the MTHFR genotype might be of prognostic significance in colorectal carcinoma.