Epigenetic misregulation is consistent with various non-Mendelian features of schizophrenia. To date, however, few studies have investigated the role of DNA methylation in schizophrenia. In this pilot study, we used LUMA (LUminometric Methylation Assay) to assess global DNA methylation level in peripheral leukocytes in 183 schizophrenic patients and 171 blood donors. We found evidence for global hypomethylation of affected samples versus unaffected (p< 0.0001) and interestingly patients with early onset of the disease presented lower levels of DNA methylation compared to the other patients (p=0.018). Bisulfite pyrosequencing, a quantitative method to assess site-specific gene methylation, revealed hypermethylation of 5-HTT and S-COMT in SZ patients (n=76 for 5-HTT and n=52 for S-COMT) compared to controls (n=84 and 52, respectively) (p=0.023 for 5-HTT and p=0.052 for S-COMT) with a gender effect among the patients. More specifically, male SZ showed a higher degree of 5-HTT DNA methylation versus females in CpG1 and CpG2 (22.83% vs 19.62%; r1=0.39, p1=0.0005 and 21.83% vs 19.88%; r2=0.24, p2=0.0341). In addition, a positive correlation between the degree of 5-HTT methylation and age was found among SZ individuals (p=0.033). Regarding S-COMT, female SZ appeared to have a higher level of methylation vs males (43.43% versus 40.3%, p=0.012). On the other hand, MB-COMT, PRODH and DTNBP1 promoter showed no degree of DNA methylation both in patients and controls.