Narcolepsy type 1 (NT1) is caused by a loss of hypothalamic orexin-producing cells, and autoreactive CD4+and CD8+T cells have been suggested to play a role in the autoimmune mechanism. Although NT1 showed a strong association with human leukocyte antigen (HLA)-DQB1*06:02, the responsible antigens remain unidentified. We analyzed array-based DNA methylation and gene expression data for theHLAregion in CD4+and CD8+T cells that were separated from the peripheral blood mononuclear cells of Japanese subjects (NT1, N = 42; control, N = 42). As the large number of SNPs in theHLAregion might interfere with the affinity of the array probes, we conducted a comprehensive assessment of the reliability of each probe. The criteria were based on a previous study reporting that the presence of frequent SNPs, especially on the 3′ side of the probe, makes the probe unreliable. We confirmed that 90.3% of the probes after general filtering in theHLAregion do not include frequent SNPs, and are thus suitable for analysis, particularly in Japanese subjects. We then performed an association analysis, and found that several CpG sites in theHLAclass II region of the patients were significantly hypomethylated in CD4+and CD8+T cells. This association was not detected when the effect ofHLA-DQB1*06:02was considered, suggesting that the hypomethylation was possibly derived fromHLA-DQB1*06:02. Further RNA sequencing revealed reduced expression levels ofHLA-DQB1alleles other thanHLA-DQB1*06:02in the patients with NT1. Our results suggest the involvement of epigenetic and expressional changes inHLA-DQB1in the pathogenesis of NT1.