Objective To detect p16 gene DNA methylation in the plasma of patients with systemic lupus erythematosus (SLE) and its significance in the disease activity and clinical manifestations. Methods Forty-five cases of SLE and 20 healthy controls were enrolled. Promoter methylation in p16 gene was measured by methylation specific PCR (MSP) in patients' plasma, and the correlation between the methylation status and clinical manifestations and routine laboratory findings were analyzed. Results Hypermethylation of p16 gene DNA was observed in the plasma of SLE. It was found that the rate of DNA hypermethylation was significantly higher in active SLE patients (20/24, 83.33%) than that in inactive patients (9/21, 42.85%) (x2 = 8.008 b; P