Of 987 cases of gastric adenocarcinoma seen at Nagoya University School of Medicine, we found 6 rare, extremely well-differentiated advanced gastric adenocarcinomas that could not be diagnosed as malignant tumors with only H&E staining, even with repeated biopsies under preoperative endoscopy. The aim of this study was to determine whether an immunohistochemical method using p53 and Ki-67 antibody would be helpfulfor preoperative pathologic diagnosis. The cancer control cases were 16 cases of ordinary well-differentiated advanced gastric adenocarcinoma, while the gastritis control cases were 22 cases of Helicobacter pylori-positive chronic gastritis. The p53 labeling index and the localization of Ki-67+ cells showed that the special adenocarcinomas in biopsy specimens were distinct from the surrounding normal mucosa and chronic gastritis, but not from the cancer control cases. These methods are useful markers for preoperative pathologic diagnosis of extremely well-differentiated gastric adenocarcinoma, which sometimes is confused with regenerative atypical glands before operation.