In order to examine the correlation of p53 mutation with heterogeneous histological differentiation and invasiveness of gastric carcinoma, we analyzed 46 areas (three to six per case) that were different histologically and anatomically in 12 advanced gastric carcinomas, shown previously to be positive for p53 mutation, using immunohistochemical, polymerase chain reaction-single strand conformation polymorphism, and direct DNA sequencing analyses. DNA derived from different sites in nine cases had the same pattern of p53 mutation, even in cases manifesting heterogeneous histology within a single tumor. Site difference of the p53 mutation was found in three cases: two showed no mutation in superficial tumor areas but presence of mutation in deep-infiltrating areas. In contrast, one case contained a mutation in the superficial area but not in the deep-infiltrating area. These results suggest that in most cases, tumor cells forming a single advanced gastric carcinoma, even though they may present a heterogeneous histology and deep invasion, seem to be derived from the same cellular clone.