Epidemiological studies have revealed that schizophrenia is highly heritable. However, genetic studies have not fully elucidated its etiology. Accumulating evidence suggests that epigenetic alterations may provide an additional explanation of its pathophysiology. We investigated the methylation profiles of DNA in peripheral blood cells from 18 patients with first-episode schizophrenia (FESZ) and from 15 normal controls. Schizophrenia patients were confined to those at the stage of first-episode psychosis. We analyzed the DNA methylation status of 27,578 CpG sites by means of the Illumina Infinium HumanMethylation27 BeadChip array. Differentially methylated CpG sites, which were particularly abundant within CpG islands, were enriched in genes related to the nuclear lumen, to transcription factor binding, and to nucleotide binding. We also observed differential methylation of the promoters of HTR1E and COMTD1, which are functionally related to genes found to be differentially methylated in schizophrenia patients in previous studies. Our results indicate the site-specific epigenetic alterations in patients with FESZ.