Aim: DNA methylation regulates gene expression, and hypomethylation is associated with abnormal T-cell function in systemic lupus erythematosus (SLE). However, little is known about the methylation levels of the interleukin (IL)-4 and -6 promoters in SLE patients. Methods: T cells were isolated from 20 SLE patients and 10 healthy controls, activated in vitro in the presence or absence of 5-azacytidine (5-azaC), and their IL-4 and -6 transcripts were characterized using semiquantitative RT-PCR. Following bisulfate modification of their genomic DNA, the levels of DNA methylation in the IL-4 or -6 promoter were determined by nested PCR and direct sequencing. Results: The levels of IL-4 and -6 mRNA transcripts were significantly higher in SLE T cells, as compared with that in the controls. Furthermore, the treatment of healthy T cells with 5-azaC demethylated the CpG islands in the IL-4 or -6 promoter and increased IL-4 and -6 mRNA transcriptions. Importantly, the hypomethylation of the CpG islands in the IL-4 and -6 promoters displayed in SLE patients was similar to that of healthy T cells treated with 5-azaC. Finally, the hypomethylation levels of the CpG islands in the IL-4 and -6 promoters in lupus patients were significantly correlated to the IL-4 and -6 expressions. Conclusion: The hypomethylation of the CpG islands of the IL-4 and -6 promoters accrued in T cells from SLE patients and was associated with the severity of SLE at the clinic.