It has been postulated that chronic atrophic gastritis, intestinal metaplasia, and dysplasia are precancerous stages of stomach tumorigenesis. We investigated the timing of p53 alterations in these events of gastric tumorigenesis. Each of 12 cases of archived tissue containing precancerous and cancerous lesions were selected for the detection of p53 alterations. Accumulation of p53 protein was detected by immunohistochemistry. Exons 5 to 8 of p53 gene were examined for mutations by polymerase chain reaction-single strand conformation polymorphism and DNA sequencing. p53 immunoreactivity was detected in 60% of the dysplasia cases and in 60% of the cases with carcinomas. p53 gene alterations were found in 37.5% of the metaplasia cases, 58.3% of the dysplasia cases, and 66.7% of the cases with carcinomas. In 71% of the cases, mutations were shown as G:C-->A:T transition. We conclude that mutation of the p53 gene is an early event in stomach tumorigenesis.