Nonsteroidal anti-inflammatory drug (NSAID) use is a common cause of peptic ulcer. This study investigated the nature, frequency, and topographic distribution of histological abnormalities of the gastric mucosa associated with chronic NSAID use. A set of 3 to 11 mapped gastric biopsy specimens were obtained from 108 chronic users of NSAIDs and 61 controls. Each specimen was graded from 0 to 3 for each of the following features: foveolar hyperplasia, smooth muscle fibers, edema, neutrophils, intestinal metaplasia, eosinophils, mononuclear cells, mucosal hemorrhage, atrophy, and Helicobacter pylori. We found that foveolar hyperplasia, considered one of the characteristic features of chemical gastropathy, was absent in 66% of NSAID users. Foveolar hyperplasia was present in 37 NSAID users (34%) and in 10 controls (18%); prominent smooth muscle fibers were found in 51 NSAID users (47%) and 10 of the controls (16%). Concurrent H pylori gastritis obscured the histopathologic changes of NSAID use. All other parameters, including H pylori infection rate (57% v 51%) were similar in NSAID users and controls. We conclude that the histological features characteristic of NSAID users were present only in a subset of patients. No single histological feature can be used to characterize or diagnose chemical gastropathy and no simple set of diagnostic criteria can be applied for this purpose.