To investigate the role of genetic instability in the development of intestinal-and diffuse-type gastric cancers, six microsatellite loci were analysed in 98 carcinomas of the two main histotypes, at both early and advanced stages of progression, and in five preneoplastic lesions. RER+ phenotype frequency proved to be significantly higher (P=0β’013) in intestinal (23 per cent) than in diffuse cancers (5 per cent) and slightly higher in advanced (19 per cent) than in early (12 per cent) tumours. When comparing early and advanced tumours of the same histotype, a similar frequency was found for diffuse tumours (4 per cent vs. 6 per cent), and an increase from 19 to 30 per cent for intestinal cancers. Instability at more than one locus was limited to intestinal tumours and replication errors were also detected in an intestinal dysplasia. On the whole, these data suggest that genetic instability has an important and early role in gastric carcinogenesis of the intestinal type and a less important role in gastric carcinogenesis of the diffuse type. Most tumours of this panel had previously been characterized for p53 gene mutations. p53 screening was extended to all samples, to investigate the possible association between gene mutations and microsatellite instability. Analysis showed a trend (P=0β’07, Fisher's exact test) towards a negative association between these two genetic lesions in tumours of the intestinal type.