Schizophrenia is a complex and common psychiatric disorder with a polygenic inheritance. In our previous report, we showed an association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and schizophrenia in patients from Bakirkoy in Istanbul, Turkey [Sazci, A., Ergul, E., Guzelhan, Y., Kaya, G., Kara, I., 2003. Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Mol. Brain Res. 117, 104-107]. We wanted also independently to confirm this study in a gender-specific manner with schizophrenic patients from Erenkoy in Istanbul, Turkey. To investigate the role of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene in schizophrenia in a gender-specific manner, we analyzed the genotypes of MTHFR677 and MTHFR1298 of 297 schizophrenic patients and 341 healthy controls, using a polymerase chain reaction restriction fragment length polymorphism method. The MTHFR 677T allele was significantly distributed (chi2=7.312; P=0.026), between schizophrenic patients and healthy controls. The T677T genotype was overrepresented in the total schizophrenic patients (OR=1.938; 95%CI=1.133-3.315; chi2=5.996; P=0.014). Similarly, the T677T/A1298A compound genotype was the most significant one in the total schizophrenic patients (OR=2.397; 95% CI=1.327-4.330; chi2=8.821; P=0.003). The C1298C genotype was overrepresented in the total schizophrenic patients (OR=1.706; 95%CI=1.014-2.870; chi2=4.126; P=0.042). Likewise, the C677C/C1298C compound genotype was significant in the total schizophrenic patients (OR=1.689; 95%CI=0.985-2.894; chi2=3.695; P=0.055). When schizophrenic patients and healthy controls were stratified according to gender difference, the T677T genotype and T677T/A1298A compound genotype were significantly overrepresented (OR=2.184; 95% CI=1.069-4.462; chi2=4.767; P=0.029; OR=2.748; 95% CI=1.215-6.214; chi2=6.301; P=0.012, respectively) in men schizophrenic patients. However, neither the MTHFR C677T nor the A1298C polymorphisms are associated with schizophrenia in women. In conclusion, the MTHFR 677T allele and T677T, C1298C genotypes, and T677T/A1298A, C677C/C1298C compound genotypes are genetic risk factors for schizophrenia in men but not in women in a gender-specific manner.