Activation of the epidermal growth factor receptor (EGFR) has a role in oncogenesis and may correlate with prognosis. The aim of this study was to examine EGFR expression in esophageal adenocarcinoma and correlate EGFR status with pathologic and clinical prognostic features. An exploratory retrospective review of 38 patients with surgically resected esophageal adenocarcinoma was performed. All patients underwent an esophagogastrectomy with regional lymphadenectomy; 24 patients underwent primary resection and 14 patients had surgery after preoperative chemoradiation therapy. Immunohistochemical analysis was performed on paraffin-embedded tissue samples using an EGFR monoclonal antibody. Low- and moderate-grade tumors were positive for EGFR expression in 2 of 15 patients; poorly differentiated tumors were positive for EGFR expression in 13 of 23 patients (p=0.02). The median survival was 35 months (confidence interval [CI]: 29-40) for EGFR negative patients (n=23) and 16 months (CI: 10-22) for EGFR positive patients (n=13) (p=0.10). Disease recurred in 3 of 21 EGFR negative patients and 6 of 13 EGFR positive patients (p=0.06). Poorly differentiated adenocarcinomas of the esophagus demonstrated higher EGFR expression compared to low-grade tumors based upon immunohistochemical analysis. A trend toward improved disease-free and overall survival was seen in EGFR negative patients.