BACKGROUND AND OBJECTIVES: Distant metastasis resulting from carcinoma cell detachment from the primary tumor involves modification of adhesion molecules. This study was conducted to examine the correlation of E-cadherin/beta-catenin expression with survival and recurrence in ampullary neoplasms. METHODS: Patients with diagnoses of ampullary neoplasms were enrolled in the study. Demographics, operative findings, and histopathological data were collected by retrospective chart review. Expression of E-cadherin and beta-catenin were detected by immunohistochemistry. RESULTS: A total of 110 patients were enrolled in the study. Preservation of membranous staining of E-cadherin was noted in 41 (37%) patients, aberrant cytoplasmic staining in 48 (44%) patients, and complete loss in 21 (19%) patients. Loss of E-cadherin was associated with pancreatic invasion, recurrence, and poor prognosis. Membranous staining of beta-catenin was noted in 65 (59%) patients, cytoplasmic or nuclear accumulation in 16 (15%) patients, and complete loss in 29 (26%) patients. Loss of beta-catenin expression was associated with tumor markers, ulcerative type, liver metastases, and poor prognosis. Pancreatic invasion, lymph node involvement, and loss of beta-catenin expression were predictors of disease recurrence. CONCLUSIONS: Loss of the E-cadherin/beta-catenin complex is related to poor prognosis in ampullary cancer. Loss of beta-catenin is predictor of recurrence in multivariate analysis.