To elucidate the relationship between genetic alterations and cellular phenotype of differentiated-type adenocarcinomas and precancerous lesions of the stomach, we phenotyped 61 gastric tumors consisting of 33 noninvasive lesions and 28 submucosal invasive carcinomas by histochemical and immunohistochemical techniques, including analysis of mucin expression. We then analyzed loss of heterozygosity (LOH) at tumor suppressor loci, examined microsatellite instability (MSI), and compared the results according to cellular phenotype. Of the 61 gastric tumors studied, 7% (4 of 61) were classified as tumors with a gastric foveolar epithelial phenotype (foveolar-type), 8% (5 of 61) as tumors with a complete-type intestinal metaplastic phenotype (CIM-type), and the remaining 85% (52 of 61) as tumors with an ordinary phenotype (ordinary-type). Forty-two percent (26 of 61) of the tumors showed LOH on at least 1 chromosomal arm. Although LOH was rare in foveolar-type tumors, it was present at variable frequencies at each tumor suppressor loci in tumors with other cellular phenotypes. p53 overexpression was observed in 0% (0 of 4) of foveolar-type, 48% (25 of 52) of ordinary-type, and 80% (4 of 5) of CIM-type tumors. With regard to MSI, all (4 of 4) of the foveolar-type tumors were classified as having high-rate MSI (MSI-H), whereas all (5 of 5) of the CIM-type tumors were microsatellite stable (MSS). Of 52 ordinary-type tumors, 19% (10 of 52) were classified as MSI-H, 12% (6 of 52) as low-rate MSI (MSI-L), and 69% (36 of 52) as MSS. The incidence of MSI-H was found to be significantly higher in foveolar-type tumors (100%; 4 of 4) than in ordinary-type (19%; 10 of 52) or CIM-type tumors (0%; 0 of 5) (P < .01). An inverse correlation between MSI-H and p53 overexpression was also noticed (P < .01). Results suggested that each cellular phenotype followed a different genetic pathway; foveolar-type tumors followed the "mutator" pathway, characterized by MSI, CIM-type tumors followed the "suppressor" pathway, characterized by LOH of tumor suppressor loci and p53 overexpression, and ordinary-type tumors appeared to show mixed genetic alterations of both types.