The effect of hyperbaric oxygenation (HBO2) was investigated in a rat model of indomethacin-induced enteropathy. Enteropathy was induced by two subcutaneous injections of indomethacin (7.5 mg/kg) 24 hr apart. Six groups of rats (n=8) were treated with and without HBO2 (100% oxygen at 2.3 atm absolute) for 1 hr once or twice a day for 2 or 5 days. Disease activity index (DAI) and total ulcer length were measured. Other rats were randomized into two groups (n=16) with and without HBO2 (1 hr once a day) and four rats were killed in each group at 12, 24, 48, and 72 hr after the final injection of indomethacin. Serum and intestinal mucosal TNF-alpha, IL-1beta, myeloperoxidase (MPO), and iNOS expression was measured. HBO2 treatment significantly attenuated indomethacin -induced intestinal ulceration and improved DAI. Indomethacin increased MPO activity and iNOS expression, and these were reduced by HBO2 treatment, with a concomitant reduction in TNF-alpha and IL-1beta. Our data suggest that HBO2 treatment has a beneficial effect on indomethacin-induced enteropathy and this effect is possibly mediated by decreased production of TNF-alpha and IL-1beta.