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Intestinal and diffuse adenocarcinomas of the stomach differ in phenotypic properties, morphology, and growth behavior. Apoptosis (programmed cell death) is induced via specific cell-surface receptors (SC-1, Fas/APO-1/CD95) and coregulated by intracellular molecules (bcl-2, p53, etc.); the success of apoptotic processes is dependent on the expression of these signals. Differences in the expression of specific apoptosis receptors and intracellular-related signals might help to explain the molecular pathogenesis of these two types of stomach adenocarcinoma. Immunohistochemical studies were performed on frozen sections of tumor tissue using human monoclonal antibody SC-1 and murine monoclonal antibodies Fas and p53, followed by peroxidase-coupled second antibodies. To determine binding of SC-1 and Fas antibodies to stomach carcinoma cells on the molecular level, Western blot analysis was performed with cell extract preparations from stomach carcinoma cells. To investigate functional apoptotic activity, MTT assays were performed with SC-1 and Fas antibodies on stomach carcinoma cells. On frozen sections intestinal type stomach carcinoma cells demonstrate little or no expression of SC-1 and Fas receptors (4 of 17 and 1 of 17, respectively). Diffuse type stomach carcinoma cells show just the opposite: greater than 50% express SC-1 and Fas at a high level (15 of 30 and 22 of 30, respectively). Normal stomach mucosa is negative with both antibodies. Expression of p53 is positively correlated with intestinal type carcinomas (11 of 17) but not with diffuse type (5 of 30). In functional studies (MTT assay) the SC-1 and Fas antibodies react with stomach carcinoma by inducing apoptosis and inhibiting growth. On Western blot analysis of extracts from stomach carcinoma cells, SC-1 detects a protein of 50 kilodalton (kD) and Fas proteins of approximately 30, 45, and 60 kD. These data indicate that gastric carcinoma cells of the intestinal and diffuse type differ in their expression of the apoptotic receptors SC-1 and Fas and the tumor suppressor gene product p53. These new data on phenotypic differences support the hypothesis that these two types of stomach carcinoma do not only differ in morphology, growth pattern, and risk factors but also in genetic pathways. Cancer 1997; 79:433-40. © 1997 American Cancer Society.