Objective: Prostate cancer is a multifactorial inherited disease affecting one in six men in industrial countries. A number of mutations in key proteins of the cell cycle machinery or signal transduction pathways have already been associated with prostate cancer; but recently, a number of polymorphisms in proteins that function in less popular cellular pathways have been investigated as possible risk factors. In this study, we evaluated the effects of two gene polymorphisms in enzymes functioning in distinct metabolic pathways on prostate cancer susceptibility. Material and Methods: Allele and genotype associations of the COMT Val108/158Met and MTHFR C677T gene polymorphisms were studied in a total of 112 Turkish prostate cancer patients who constituted our study group while 145 healthy males constituted our control group. Genomic DNA was isolated from the peripheral blood leukocytes of the subjects and analyzed by two different real-time polyrnerase chain reaction assays. Results: The frequency of the heterozygous COMT G/A and the homozygous MTHFR TIT genotypes were higher in the study group compared to the control group (47.3% versus 34.5%; and 14.3% versus 7.6%, respectively). Prostate cancer subjects with the heterozygous MTHFR C/T genotype had higher prostate specific antigen values. Nevertheless, no statistically significant association was found between these polymorphisms alone or in combination and the risk of developing prostate cancer. Conclusion: We suggest that functional gene polymorphisms in metabolic proteins predispose subjects to increased risk of developing cancer; but, not as strong as mutations in proto-oncogenes or tumor-suppressor genes.