Sixty-three cases of stomach resections harboring both adenoma and carcinoma were analyzed for microsatellite instability (MSI). The cases included 28 carcinomas arising from adenoma (Type I) and 35 carcinomas with separate adenoma (Type II). The results of MSI assessed by 49 markers were the same for BAT-26 instability. The incidence of MSI was 21% in gastric adenoma and 30% in gastric carcinoma, which is significantly higher than gastric carcinoma without associated adenoma (p < 0.01). Five of eight (63%) cases of multiple carcinomas associated with adenoma showed MSI+ in adenoma and in one or more carcinoma lesion(s). Eight of thirteen (62%) MSI+ adenomas were associated with carcinoma, whereas 20 of 50 (40%) MSI adenomas were associated with carcinoma. MSI+ adenomas of Type I showed a higher mutation rate of the TGF-beta RII gene than Type II (88% versus 40%). Gastric adenoma with TGF-beta RII gene mutation was more prone to transform into carcinoma (p = 0.03). This study revealed that gastric carcinoma arising from adenoma is frequently associated with a mismatch repair deficiency mechanism. In the gastric adenoma-carcinoma sequence, TGF-beta RII gene mutation occurred early in the adenoma stage and it persisted after malignant transformation.