Free radical damage in reflux esophagitis of rats induced by 24-hr duodenojejunal ligation was studied. Oxygen free radicals were selectively blocked. Groups were: sham operation, reflux, reflux + superoxide dismutase (SOD), catalase, dimethylthiourea, allopurinol, and inactivated SOD or inactivated catalase alone or in the combination SOD + catalase or SOD + catalase + dimethylthiourea + allopurinol. Macroscopic esophagitis was inhibited only by SOD, alone or in combination with other agents. Esophageal mucosal lipid peroxidation was 10-fold increased in the reflux group compared to the sham group (P < 0.05). This response was damped by SOD > catalase (P < 0.05) but not by the inactivated enzymes, dimethylthiourea or allopurinol. SOD + catalase showed no significant improvement on SOD alone. Total inhibition of lipid peroxidation was achieved by combining all scavengers. Total glutathione (GSH) in the esophageal mucosa was stimulated by reflux. This response was inhibited by scavengers equivalent to their efficacy in preventing lipid peroxidation. It is concluded that reflux esophagitis is associated with free radical release with O2- being the main source. Free radicals appear to stimulate GSH production in this prolonged oxidative stress.