BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system abnormally reacts against cells and tissues leading to inflammation. Epigenetic alterations, including DNA methylation and histone modification, have critical effects on autoimmune disease and SLE pathogenesis via dysregulation of critical genes. AimsThe purpose of this study was to evaluate the epigenetic-related gene expression of DNA methyltransferase (DNMT) and histone deacetylase 1 (HDAC1) in Iranian patients with SLE. MethodsThis matched case–control study included 16 people with SLE and 16 healthy people who were referred to the Rafsanjani rheumatology clinic, in southeast Iran. The expression of DNMT and HDAC1 genes was measured through a real-time PCR assay of blood samples. ResultsDNMT gene expression did not differ significantly between SLE and healthy groups (P=0.21). In contrast, HDAC1 gene expression was enhanced in the SLE group, but this enhancement failed to reach statistical significance (P=0.94). ConclusionThe results of this study suggest that overexpression of HDAC1 could serve as a diagnostic for SLE disease. Additional studies with larger sample sizes are required to confirm our findings. Evaluation of other genes related to SLE disease is essential and may help to make an accurate diagnosis of the disease.