OBJECTIVES: Common genetic SNPs in two genes, encoding catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR), which are interconnected with COMT gene regulation, have been reported to contribute to schizophrenia risk. In this study, we evaluated the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk with a case-control study in a Korean population. METHODS: We performed a case-control study by genotyping analysis using 360 cases and 348 controls in Korean subjects to determine the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk. RESULTS: Four functional SNPs in COMT (Val158Met and rs165599) and MTHFR (C677T and A1298C) were genotyped by primer extension assay. None of the genotype distributions for the four SNPs was significantly different between cases and controls. Stratified analysis did not show any significant gender difference for any polymorphism. In addition, we found no evidence of a gene-gene interaction in the analysis of combined genotypes. CONCLUSION: Our results suggest no significant association between the selected functional polymorphisms of COMT or MTHFR in Korean schizophrenia subjects. However, further studies are required to confirm our findings in a larger number of subjects.