Into the Heidenhain pouches of 3 dogs 30 ml of 0.1N HCl was instilled and removed at 30-minute intervals for 6 hours. During the 3rd and 4th periods the acid instillate contained 4.5 mg/ml or 12.4 mM of ASA, indomethacin or fenoprofen. All 3 agents affected the functional integrity of the mucosal barrier, but the characteristics of their actions were different. The H+ concentration was decreased by ASA and fenoprofen and increased by indomethacin when the instillate contained drug. All 3 drugs increased the net flux of Na+, K+, Ca++ and Mg++. Following initial augmentation of instillate volume and H+ concentration, indomethacin caused sustained back diffusion of acid from lumen to mucosa; this was accompanied by mucosal bleeding. Peak effects of ASA on the net flux of ions occurred during or immediately after drug infusion and were greater than those of indomethacin and fenoprofen. Fenoprofen at 12.5 nM had no effect on concentrations of Ca++ and Mg++ while both were significantly increased by equal molar dose of ASA or indomethacin. In onset of action indomethacin was slow but once disruption of functional integrity started, it continued for hours showing no signs of returning to normal condition. In this sense, the total disruptive action of an equal weight or molar dose of indomethacin was greater than that of ASA or fenoprofen. At pH 1, the absorption of ASA from the Heidenhain pouch was greater than that of indomethacin and fenoprofen; their respective concentrations in the plasma were 53.9, 14.2 and 13.7 mumol.