OBJECTIVE Benign tumors and tumor-like conditions in the ampullary area are uncommon, and there are extremely rare cases of adenomyoma (AM) and adenomyomatous hyperplasia (AMH). Surgical treatment is necessary if these lesions cause biliary obstruction. In addition, the differential diagnosis of AM and AMH from carcinoma is often difficult by standard endoscopic biopsy and cytopathological analysis that may show differential findings, resulting in unnecessary surgeries sometimes being performed. METHODS Immunohistochemical (IHC) analysis of periampullary AM and AMH was performed. RESULTS For both types of lesions, epithelial glandular cells (EGCs) showed diffuse expression of MUC6 and focal expression of HIK1083, mainly in the inner region, and focal expression of MUC5AC, mainly at the surface. The EGCs showed no expression of MUC1 or MUC4, both of which were identified as malignant tumor markers in our previous series of mucin expression studies in pancreatobiliary tumors. The expression of CK7, which was diffusely positive in normal periampullary mucosa, was decreased in the EGCs of AM and AMH. CONCLUSIONS A combined evaluation of IHC findings may be effective in the detection of AM and AMH, and also in distinguishing benign periampullary lesions, such as AM and AMH, from ampulla of Vater adenocarcinoma, thus avoiding excessive surgery.