The objective of this study is to investigate the levels of interleukin (IL)-21 and autoantibodies (AAbs) against IL-21 and their association with clinical characteristics and laboratory parameters in patients with rheumatoid arthritis (RA). One hundred twenty-six patients with RA, 69 patients with osteoarthritis (OA), and 88 healthy controls (HC) were included in this study. The levels of IL-21 and AAbs against IL-21 in the serum were measured using enzyme-linked immunosorbent assay (ELISA). The correlation between the levels of IL-21 and anti-IL-21 AAbs with clinical and laboratory parameters was evaluated. The results showed that the concentration of IL-21 was significantly higher in the serum of patients with RA (15.58 +/- 3.22 ng/ml) than OA (1.80 +/- 0.99 ng/ml) and HC (0.07 +/- 0.03 ng/ml, p < 0.01). The levels of IL-21 in the serum correlated with erythrocyte sedimentation rate (ESR) in patients with RA (r = 0.435, p < 0.01). Anti-IL-21 AAbs could be detected in RA patients. The median AU value of AAbs against IL-21 was significantly higher in serum of RA (47.90) than in that of OA (15.17) and HC (8.19, p < 0.01). The titers of AAbs against IL-21 correlated with Disease Activity Score-28 (DAS28) (r = 0.449, p < 0.001), ESR (r = 0.386, p < 0.001), and CRP (r = 0.241, p = 0.03). Both IL-21 and AAbs against IL-21 are elevated in RA. The levels of AAbs against IL-21 correlate with disease activity, which suggests that anti-IL-21 AAbs may play a role in the pathogenesis of RA.