The expression of TGF alpha and c-Ha-ras p21 was studied immunohistochemically in a total of 174 gastric carcinomas, comprising 27 early carcinomas and 147 advanced carcinomas. TGF alpha-immunoreactivity was detected in 7 (25.9%) of the 27 early carcinomas and in 110 (74.8%) of the 147 advanced carcinomas, the incidence being significantly different between the two (P less than 0.01). Out of the 67 c-Ha-ras p21 positive carcinomas, 59 (88.1%) showed TGF alpha-immunoreactivity synchronously. A significant positive correlation was observed between the grade of TGF alpha and incidence of c-Ha-ras p21-immunoreactivity in tumor cells (P less than 0.01). Furthermore, a good correlation was demonstrated between synchronous expression of TGF alpha and c-Ha-ras p21 and depth of tumor invasion (P less than 0.01). The incidence of synchronous expression of TGF alpha and c-Ha-ras p21 in metastatic tumors was significantly higher than that in primary tumors showing no lymphatic metastasis (P less than 0.01). Patients with carcinomas showing synchronous expression of TGF alpha and c-Ha-ras p21 had an extremely poorer prognosis than those without TGF alpha and c-Ha-ras p21. These results indicate that the synchronous expression of TGF alpha and c-Ha-ras p21 plays an important role in high malignancy of gastric carcinomas.