Inactivation of the E-cadherin gene has been described previously in gastric carcinomas. In the present study, we investigated the alterations of the E-cadherin gene in gastric carcinomas and analyzed the relationship between such alterations and the histotypes of the tumors. We performed PCR/single-strain conformation polymorphism mutation screening and loss of heterozygosity analysis of the E-cadherin gene in a series of 26 gastric carcinomas, including 10 "pure" intestinal, 10 "pure" diffuse, and 6 mixed gastric carcinomas, the latter with intestinal and diffuse components. Fifteen mutations of the E-cadherin gene were identified in 12 cases (46.2%). Mutations included 10 missense mutations, 7 of which occurred in sequences coding for calcium binding motifs, 3 splice site mutations, 1 nonsense mutation, and 1 frameshift deletion. We found mutations of the E-cadherin gene in 7 of 10 "pure" diffuse carcinomas (70.0%) and in 5 of 6 mixed carcinomas (83.3%). No mutations were found in "pure" intestinal carcinomas. In mixed carcinomas, inactivating E-cadherin mutations were exclusively observed in the diffuse component of the tumors. We conclude that E-cadherin inactivation is significantly related with the diffuse histotype in gastric carcinomas, not only in "pure" diffuse carcinomas but also in the diffuse component of mixed tumors. To the best of our knowledge, this is the first report advancing a genetic basis for the phenotypic divergence of mixed gastric carcinomas.