SUMMARY. A variety of strategies, using chemotherapy, radiation therapy, and surgical resection have been employed in the treatment of locally advanced esophageal cancer. No strategy has proven superior, and poor long-term survival is anticipated. A survival benefit has been suggested for patients who achieve a pathologic complete response (pCR) following neoadjuvant chemoradiation therapy. We examined the collective results at three institutions of patients who achieved a pCR following neoadjuvant chemoradiation therapy. A retrospective, chart-based review was conducted. Kaplan-Meier calculations were used to determine overall and disease-free survival. Between 1995 and 2002, 229 patients were treated with neoadjuvant chemoradiation followed by surgery as a planned approach for locally advanced esophageal cancer. Forty-one patients (18%) demonstrated pCR and were the focus of this study. Histology was adenocarcinoma in 29, squamous in 10, and adenosquamous/undifferentiated in two patients. Forty patients were staged by endoscopic ultrasound prior to neoadjuvant therapy and all demonstrated a T-stage of 2 or higher, while 19 had evidence of nodal metastasis. Four patients died in the perioperative period. The remaining patients have been followed for an average of 46 months. Overall survival at 5 years was 56.4% and a median survival has not been reached. Esophageal cancer patients who demonstrate a pCR following neoadjuvant chemoradiation are a select subset who demonstrate excellent long-term survival. Identification of clinical variables or biomarkers predictive of pCR may therefore optimize treatment strategies of patients with locally advanced esophageal cancer.