Studies in animal models of lupus have reported increased production of IL-21 in MRL/lpr or BXSB mice and attenuation of autoimmune features in mice treated with IL-21 blocking agents. Little is known about IL-21 production and function in patients with systemic lupus erythematosus (SLE). We determined IL-21 levels in serum samples from 28 patients with SLE, 8 disease and 16 healthy controls by ELISA. Mean level of IL-21 was significantly higher in SLE patients (440±372 pg/ml) compared to normal controls (114 ± 101 pg/ml; p=0.05) and inversely correlated with C3 levels. Furthermore, patients with active disease (SLEDAI >4) had higher levels of serum IL-21 (1332.7±1084pg/ml) than patients with inactive disease (217.6±184 pg/ml). IL-21 and IL-21R expression was determined on ex vivo and in vitro stimulated CD4+ T cells by RT-PCR and immunostaining. IL-21 mRNA expression was 7 fold higher in ex vivo CD4+ T cells while intracellular levels were higher in stimulated memory CD4+ T cells from lupus patients compared to controls. IL-21R expression was upregulated on in vitro stimulated CD4+ T cells in both patients and controls. CD4+ T cells from lupus patients had equal susceptibility to proliferative effects induced by IL-21 when compared with controls. Similarly, lupus B cells were equally responsive to IL-21 when compared to controls with respect to proliferation, plasma cell differentiation, IgG and IL-10 production. In conclusion, elevated levels of IL-21 in lupus patients may promote auto-reactive CD4+ T cells proliferation as well as B cell proliferation and differentiation, thus contributing to the generation of T cell dependent autoreactive B cell responses.