Background: Polymorphisms of the gene encoding methylenetetrahydrofolate reductase (MTHFR) have been studied widely in various cancers, excluding thyroid cancer. However, reports on the association of various polymorphisms with certain cancers are contradictory. Materials and Methods: We have investigated whether the prevalence of the most common polymorphism (C677T) in the MTHFR gene has any link with various cancers, using genomic DNA and polymerase chain reaction restriction fragment length polymorphism (PCRRFLP) analysis. Results: The frequency of the heterozygous variant (677CT) but not that of 677TT was found to be significantly higher in colorectal cancer cases than in controls (p < 0.039; odds ratio 2.35 and 95% confidence interval 1.02–5.415). The frequencies for 677CT were 11.0 and 5.0% in colorectal cancer samples and controls, respectively. In ovarian cancer, the frequency of the 677TT variant was 6.0% which differed significantly (p < 0.026) from the control value of 1.0%. However, the frequencies of the variants in cervical, thyroid, and breast cancer cases did not differ from controls. Conclusions: Our data taken together with other reports indicates that the polymorphism C677T of MTHFR is a risk factor for developing colorectal cancer but not cervical, thyroid, and breast cancers. The present study also reconfirms that frequencies of the variants are not gender-specific.