The expression of p185erbB2 and p21ras was determined immunohistochemically in normal mucosa, intestinal metaplasia, dysplasia and in intestinal and diffuse type carcinoma of the stomach. The positive rates of p185erbB2 and p21ras in intestinal type were significantly higher than those of diffuse-type carcinoma. The results indicate that there are differences not only in clinical and biologic features, but also in molecular abnormalities between the two types of stomach cancer. Positive staining of cell membrane for p185erbB2 was observed specifically in intestinal type cancer, but not in the other lesions. Positive expression of p185erbB2 on the cell membrane appears to be a useful marker in identification of malignant change of gastric mucosa, as well as a late event of gastrocarcinogenesis. The results of in situ hybridization analysis in cancer tissues were consistent with those obtained by immunohistochemistry and demonstrated amplification of erbB2 gene at the mRNA level. No significant difference of p21ras expression was found among intestinal metaplasia, dysplasia, and intestinal type carcinoma; therefore, it might not be a specific marker of malignancy in gastric mucosa. Expression of p21ras may be an early event in the development of lesions predisposing to carcinoma.