Adenosine is considered as a potent endogenous anti-inflammatory and immunosuppressive molecule. We examined the roles of A2A-adenosine receptor (A(2A)R) in the progression of lupus nephritis. MRL/lpr mice were given a selective A(2A)R agonist, CGS21680 (0.4 mg/kg per day, i.p.) while control mice received saline only. After 8 weeks of treatment, mice were sacrificed for assessment of functional and histological parameters as well as inflammatory infiltration in the kidneys. MCP-1, IFN-γ, MHC-II and A(2A)R mRNA expression was evaluated by RT-PCR. Expression of A(2A)R and nuclear NFκB p65 protein was determined by Western blot analysis. Levels of anti-dsDNA antibody and IFN-γ were measured by ELISA. CGS21680 treatment resulted in significant decrease in proteinuria, blood urea and creatinine as well as improvement in renal histology. Renal macrophage and T-cell infiltration were significantly attenuated in association with suppressed expression of MCP-1, IFN-γ and MHC-II. CGS21680 treatment reduced the level of serum anti-dsDNA and renal immune complex deposition. CGS21680 inhibited the activation of NFκB and suppressed the expression of IFN-γ, MCP-1 and MHC-II in MRL/lpr splenocytes. A(2A)R activation suppressed inflammation in the kidneys of MRL/lpr mice and can be considered as a novel therapeutic approach for human lupus nephritis.