The occurrence of systemic lupus erythematosus (SLE) involves a gene-environment interaction and epigenetic regulations, such as DNA methylation, may play important role in the etiology of SLE. Some neurotransmitters, such as serotonin, can regulate T- and B-cell proliferation via the 5-HT1A receptor and are involved in the pathology of SLE. The abnormal methylation of DNA has been reported in SLE, but there has been no study concerning the serotonin system. This study was conducted to explore the DNA methylation status of the promoter region of HTR1A (PR-HTR1A) and the level of HTR1A mRNA in the peripheral blood lymphocytes (PBLC) of SLE patients and healthy controls (HC). In this study, the DNA methylation status of PR-HTR1A and the level of HTR1A mRNA were detected in the PBLC of SLE patients and HC. The results showed significant hypomethylation of PR-HTR1A in SLE patients compared with HC. The patients also showed a significantly higher HTR1A mRNA level than did the controls. Relatively higher percentage of anti-histone antibodies in methylated SLE patients was found compared with unmethylated patients. Our results support the hypothesis that the hypomethylation of PR-HTR1A and overexpression of HTR1A might contribute to SLE. These results also reveal that epigenetic regulation via the serotonin system may contribute to SLE, and reveal the link between the brain and the immune system. Lupus (2011) 20, 678-689.