To determine the chronology of p53 mutation in the gastric carcinogenic sequence, we studied p53 overexpression in premalignant lesions, including 17 adenomatous polyps (10/17 surrounded by intestinal metaplasia and 11/17 harboring foci of adenocarcinoma or severe dysplasia), and 18 hyperplastic polyps (4/18 with focal adenomatous changes). Immunohistochemistry with PAb 1801 monoclonal antibody was performed on archival material; p53 nuclear staining was seen in 10/17 adenomas, but was limited to the foci of adenocarcinoma in three cases. Five adenomas with foci of severe dysplasia or carcinoma were nonreactive. Intestinal metaplasia, normal gastric mucosa, and 14/18 hyperplastic polyps were nonreactive. p53 Reactivity observed in four hyperplastic polyps was limited to adenomatous foci. These results suggest that p53 overexpression occurs in dysplastic epithelium of precancerous gastric lesions. Its absence in chronic atrophic gastritis with intestinal metaplasia suggests it is a relatively late event in the gastric carcinogenic sequence.