To study the process of gastric mucosal adaptation to aspirin administration, 14 normal men underwent a study with continued administration of aspirin. Endoscopic assessment, biopsies, and gastric wash collections for acid, mucus, and deoxyribonucleic acid recovery were performed weekly; aspirin was continued until the endoscopy showed minimal damage. Six subjects took 650 mg of aspirin b.i.d., and 8 took 650 mg q.i.d.; adaptation and resolution took longer with the higher dose (median 4.5 wk vs. 1 wk, p less than 0.01). Despite improvement in mucosal appearance, gastric microbleeding remained elevated throughout aspirin administration. In contrast, deoxyribonucleic acid recovery (a marker for cellular exfoliation and regeneration) increased significantly just before the time of resolution, when, on average, it more than doubled. As no other biochemical or histologic changes could be associated with the resolution of damages, we conclude that gastric adaptation to chronic injury may involve increased cellular regeneration.