Growing evidence indicates that adenosine receptors could be promising therapeutic targets in autoimmune diseases. Here we studied the role of adenosine receptors in controlling the course of type 1 diabetes. Diabetes in CD-1 mice was induced by multiple-low-dose-streptozotocin (MLDS) treatment and in nonobese diabetic (NOD) mice by cyclophosphamide injection. The nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) prevented diabetes development in both MLDS-challenged mice and in cyclophosphamide-treated NOD mice. The effect of NECA was reversed by the selective A 2B receptor antagonist N-(4-cyanophenyl)-2-[4-(2, 3, 6, 7-tetrahydro-2, 6-dioxo-1, 3-dipropyl-1H-purin-8-yl) phenoxy] acetamide (MRS 1754). The selective A 1 receptor agonist 2-chloro-N 6-cyclopentyladenosine (CCPA) and A 3 receptor agonist N 6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA) were less efficacious in ameliorating the course of diabetes. NECA inhibited diabetes in A 2A receptor KO mice and the selective A 2A receptor agonist 2-p-(2-carboxyethyl) phenethyl-amino-5′-N-ethyl-carboxamidoadenosine (CGS21680