Inhibition of gastric H+ secretion by phenylbutazone and indomethacin was investigated by examining the effects of these agents on a putative H+ transport enzyme, a K+ stimulated ATPase. unique to gastric mucosa. Phenylbutazone and indomethacin were found to inhibit both the K+ ATPase and the K+ pNPPase. Kis were 430 μM and 710 μM for the K+ ATPase and 330 μM and 670 μM for the K+ pNPPase for phenylbutazone and indomethacin respectively. Inhibition was not reversed by Mg2+, ATP, pNPP, or KCl and obeyed non-competitive kinetics. Inhibition of the pNPPase suggested that the mechanism of inhibition involved the K+ sensitive dephosphorylation of the phosphoenzyme. In the presence of 500 μM phenylbutazone dephosphorylation was significantly less at 3, 5, 7.5, 10 and 15 sec following KCl addition. These studies provide an alternate mechanism for inhibition of gastric H+ secretion by phenylbutazone and indomethacin. © 1977.