Coadministration or preadministration of acetaminophen with aspirin affords partial protection against aspirin-induced gastric mucosal injury in animals. Recently, it was reported that preadministration of acetaminophen in humans yielded similar protection. That study used pylorus occlusion, intravenous atropine, and exogenous acid, and thus may not have mimicked the usual clinical situation. We studied a clinical regimen, in 7 normal volunteers. We coadministered acetaminophen (1.95 or 2.6 g/day) and aspirin (in a 1:1 ratio) and used gastroscopy to evaluate if there was gastric mucosal protection. Aspirin alone was used as a positive control. We found the expected significant increase in mucosal damage associated with increasing aspirin dose (p less than 0.05) comparing the lowest and highest aspirin doses (1.95 g vs. 3.9 g) after 7 days of continuous therapy. There was no difference in the degree of mucosal injury when receiving the same dose of aspirin (p = 0.38) whether or not acetaminophen was administered in a dose equal to that of aspirin. Thus, in a more normal clinical situation, we were unable to confirm the findings from the pylorus-occluded model, i.e., we failed to identify either a beneficial effect, or a trend, for protection from gross mucosal damage by the coadministration of acetaminophen and aspirin in equal dosages.