Esophageal adenocarcinoma is a virulent malignancy that is rapidly increasing in incidence. Overexpression of p53, a tumor-suppressor gene with prognostic significance in many malignancies, has not been adequately evaluated in this disease. The purpose of this study was to evaluate the pattern and importance of p53 protein accumulation in patients with esophageal adenocarcinoma. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue from 24 patients, all of whom had early stage disease. Nineteen of 24 patients underwent surgery, and 16 had complete tumor resection. p53 oncoprotein immunoreactivity was demonstrated in 50% (12/24) of patients overall and 50% (8/16) of patients undergoing esophagectomy. p53 overexpression was more common in patients with well-differentiated tumors (P = 0.07). The tissue surrounding tumor stained positive for p53 in six patients, four of whom had no evidence of Barrett's epithelium. Among the 16 patients who underwent esophagectomy, those whose tumors demonstrated p53 overexpression had a longer overall (28 vs. 13.5 months) and disease-free (24.3 vs. 13 months) median survival. The difference in disease-free survival was significant (P = 0.05). Our findings suggest that p53 overexpression may serve as a marker of improved survival in patients with esophageal adenocarcinoma.