This study evaluated the effects of the adenosine A₃ receptor agonist, N⁶-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA), in two murine models of colitis, the dextran sodium sulphate-induced colitis and the spontaneous colitis found in interleukin-10 gene deficient mice. IB-MECA was given orally twice a day at a dose of either 1 or 3 mg/kg/day. Evaluation of colon damage and inflammation was determined grossly (body weight, rectal bleeding) and biochemically (colon levels of myeloperoxidase, malondialdehyde, chemokines and cytokines). There was significantly increased inflammatory cell infiltration into the colon associated with an increase in colon levels of cytokines and chemokines; with subsequent free radical related damage in both dextran sodium sulphate-induced colitis and 10-week-old interleukin-10^−/− mice. IB-MECA protected in both models against the colitis induced inflammatory cell infiltration and damage and attenuated the increases in colon inflammatory cytokine and chemokine levels. Thus activation of the adenosine A₃ receptor is effective in protecting against colitis.