The mechanism of gastric mucosal adaptation to continued aspirin (ASA) administration is unknown. We have investigated growth and proliferation markers in healthy subjects under prolonged ASA treatment. In eight healthy volunteers, ASA treatment (2 g/day) was continued for 14 days. Endoscopy was performed before medication; at days 3, 7, and 14 of ASA treatment; and at days 16 and 18 (2 and 4 days, respectively, after medication was ceased). Gastric biopsies from oxyntic and antral mucosa were studied by histology and by histochemistry for proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), and epidermal growth factor receptor (EGFr). ASA treatment did not change the expression of EGF and EGFr significantly. The PCNA index showed local inconsistent variations. However, increased TGF-alpha expression after ASA was noted, particularly in hyperplastic surface epithelium. Edema and teleangiectases were common in gastric mucosa after ASA. An increasing incidence of foveolar hyperplasia was also noted in the antral mucosa. Healthy subjects on prolonged ASA treatment gradually develop parameters of chronic reactive gastritis accompanied by increased TGF-alpha expression in gastric surface epithelial cells, especially in hyperplastic areas.