In this study, we examined the effect of nimesulide and ranitidine on the indomethacin- and ibuprofen-induced ulcer. In addition, we investigated whether there was a direct chemical interaction of nimesulide and ranitidine with indomethacin, and also whether nimesulide and ranitidine neutralized the gastric acid in vitro. Our studies showed that nimesulide (100, 300, 500 mg/kg) prevented the indomethacin-induced gastric ulcers completely. Ranitidine at a dose of 150 mg/kg reduced the mean ulcer area to 2.5 +/- 0.76 mm2 in the indomethacin-treated and to 2.0 +/- 0.81 mm2 in ibuprofen-treated rats. The mean ulcer areas in rats given only indomethacin and only ibuprofen were 20.3 +/- 1.58 mm2 and 9.5 +/- 1.43 mm2, respectively. There were no chemical reactions between nimesulide and indomethacin or ranitidine and indomethacin in vitro. Nimesulide and ranitidine did not neutralize the gastric acid in vitro.