Aspirin was administered intravenously to study its effect upon gastric mucosa at high blood levels in the therapeutic range for rheumatic diseases. Five healthy volunteers were studied twice each with intravenous aspirin (3 g over 2 hr) and isotonic saline infusion as control. In one study, gastric potential difference was measured; in the other, coded gastric biopsies were taken sequentially prior to infusion, and at the end of infusion. Duplicate biopsies were taken for light and scanning electron microscopy. Mean potential difference at the end of the intravenous aspirin infusions was -47.7 +/- 1.4 mV, compared with saline, -51.1 +/- 2.5 mV (P greater than 0.05). The percentage of cells damaged after 2 hr intravenous infusion of aspirin (3.2 +/- 0.4%) was not significantly different from that after intravenous saline (2.6 +/- 0.3%). In contrast to oral aspirin, acute administration of aspirin parenterally does not produce detectable histological damage in man, nor does it significantly alter gastric mucosal potential difference. We conclude that high blood levels of circulating salicylate do not acutely damage gastric mucosa. Thus, histologic gastric mucosal damage produced acutely after single oral doses of aspirin are due to its topical, rather than systemic, action.