The nature and time-course of acute piroxicam-induced gastric mucosal injury was determined in ten healthy volunteers treated with 10 mg piroxicam twice daily by mouth for 21 days. Mucosal injury was measured endoscopically by visual analogue scales and by the method of Lanza, and luminal blood loss by haemoglobin measurements in gastric washings, 10 h after the first drug dose and then after 5, 10 and 21 days. Acute mucosal injury, consisting mainly of haemorrhagic lesions in the gastric body, developed to a maximum extent within 10 h of the first dose of piroxicam, and did not increase thereafter. By contrast intraluminal bleeding increased little for 10 days and then rose significantly at 21 days, when plasma piroxicam levels reached values likely to affect platelet function. We conclude that gastric mucosal injury and bleeding may be dissociated and may constitute different targets for prophylaxis. Gastric mucosal injury is probably exerted topically as it is maximal at low plasma drug concentrations, whereas bleeding may arise because of interference with platelet-dependent mechanisms.