This study aims to investigate the serum IL-21 levels in systemic lupus erythematosus (SLE) and its relations with clinical and laboratory features. Fifty-seven patients with SLE and 30 healthy volunteers were recruited in the current study. Serum IL-21 levels were detected by enzyme-linked immunosorbent assay. Statistical analyses were performed by SPSS 10.01. Results showed that IL-21 levels were significantly decreased in the serum of patients with SLE compared with controls (P = 0.026). There was no significant difference regarding serum IL-21 level between SLE patients with nephritis and those without nephritis (P = 0.066); no significant difference was found between less active SLE and more active SLE (P = 0.588). The presence of anemia was associated with low serum IL-21 levels (P = 0.030) in SLE patients. In summary, decreased serum level of IL-21 and its association with anemia indicate a possible role of IL-21 in human SLE. However, further studies are needed to confirm this preliminary results.