Interleukin-22 (IL-22) and IL-22-producing T helper (Th) cells are involved in the pathogenesis of autoimmune diseases. However, the roles of IL-22 and IL-22-producing T helper cells in systemic lupus erythematosus (SLE) remain unclear. Plasma levels of IL-22 were measured in 41 patients with SLE (19 new-onset and 22 relapsing patients) and 20 healthy controls by enzyme-linked immunosorbent assay (ELISA). Meanwhile, the percentages of CD4+IFN-γ+ (Th1), CD4+IL-17+ (Th17) and CD4+IFN-γIL-17 IL-22+ (Th22) cells in peripheral lymphocytes were determined by flow cytometry, and plasma IL-22 autoantibodies were detected by ELISA in 19 new-onset SLE patients and 20 healthy controls. Plasma IL-22 levels in new-onset SLE patients were significantly decreased compared with relapsing SLE patients and healthy controls. After treatment with prednisone and hydroxychloroquine, the levels of plasma IL-22 in new-onset SLE patients were obviously increased but still lower than healthy controls. There was a positive correlation between plasma IL-22 levels and the percentages of Th22 cells, but not Th1 and Th17 cells. Moreover, plasma IL-22 levels as well as peripheral Th17 and Th22 cells correlated with SLE disease activity index (SLEDAI) scores and erythrocyte sedimentation rate (ESR). High frequencies of plasma IL-22 autoantibodies were detected in new-onset SLE patients. However, IL-22 levels did not correlate with IL-22 autoantibody. Decreased plasma IL-22 levels and correlation with Th22 cells may be distinct features in new-onset SLE. Moreover, IL-22 and Th22 cell correlated with SLE disease activity.