Although the mechanism remains obscure, two histological subtypes of gastric carcinoma (GC), the diffuse and intestinal types, differ drastically in epidemiological, clinical, pathological and biological characteristics. We investigated whether the genetic alterations of several oncogenes and tumour suppressor genes could be correlated with the two histological subtypes. In 60 patients with GC, the overexpression of mutant p53 and c-erbB-2 oncoproteins was studied using immunohistochemical stains. Mutations of the p15 and p16 tumour suppressor genes were assessed by polymerase chain reaction, Southern blotting, and direct DNA sequencing. Overexpression of c-erbB-2 and p53 was found in 21 (35.0%) and 27 (45.0%) patients, respectively. Overexpression of the c-erbB-2 oncoprotein was more common in the intestinal type (15/32, 46.9%) and the advanced stage (19/45, 42.2%) than in the diffuse type (6/28, 21.4%) and the early stage (2/15, 13.3%) of GC (P<0.05). Similarly, p53 overexpression was more frequently found in the intestinal type (19/32, 59.4%) and the advanced stage (24/45, 53.3%) than in the diffuse type (8/28, 28.6%) and the early stage (3/15, 20.0%) of GC (P<0.05). Homozygous deletions of p16 in exon 1 were found in six (10.0%) patients. Five of them had the intestinal-type advanced GC. Neither point mutations of p16 nor alterations of p15 were detected. The frequency of alterations of p53, c-erbB-2, and p16 was not related to sex and Helicobacter pylori infection. No correlation of genetic changes between any two genes was observed. Our preliminary results indicate alterations in the p15 gene were not important in gastric tumorigenesis, while infrequent homozygous deletions in the p16 gene play a limited role in tumour progression of intestinal-type GC. Moreover, overexpression of c-erbB-2 and p53 is frequently encountered in the intestinal-type advanced GC. Alterations of p53, c-erbB-2 and p16 genes may function independently of each other in gastric carcinogenesis. The association between genetic alterations and histological subtypes supports the notion that a distinct pathogenesis may exist in different histological subtypes.