Gastric cancer shows remarkable heterogeneity in histological pattern, cellular phenotype, and genotype. Tumor subsets identified by varying procedures have shown limited reciprocal correlation and have failed to provide a sound rationale for the characterization and classification of all tumors. Based on a case series of 130 gastric cancers that covered both early (70 cases) and advanced (60 cases) stages and that represented most histological types and structural patterns, this study investigated (1) microsatellite instability and p53 gene mutation by means of PCR-based molecular techniques and (2) p53 protein accumulation or tumor cell immunophenotype by means of immunoperoxidase procedures. It was found that microsatellite instability and p53 gene mutation involve two distinct subsets of both early and advanced-stage glandular (intestinal) cancer, and that, contrastingly, they leave purely diffuse cancers unaffected. Mixed cancers, namely, those in which glandular admixed with diffuse growths, showed scarce microsatellite instability at all stages, whereas prominent p53 gene mutation and p53 protein accumulation was limited to the advanced stage alone. No significant correlation was found between tumor cell immunophenotype and either genotype or histotype, although some correlation with particular structural patterns was detected. Comparison of intramucosal with invasive growths within any given tumor suggested that invasive cancers with diffuse-type growth arise in part from mucosal cancers of glandular or mixed structure through progressive loss of intercellular junctional systems. It is concluded that at least two genetically distinct subsets of glandular cancer, one with microsatellite instability and the other with p53 lesions, should be separated both from purely diffuse cancer and, at least in the advanced stage, from mixed cancer. Available evidence suggests distinct clinicopathologic profiles for such tumor entities.