Background: Controversy exists over the optimal neoadjuvant therapy in patients with locally advanced esophageal cancer (EC). While most groups favor neoadjuvant chemoradiation (nCRT), some advocate preoperative chemotherapy (nCT) without radiation. The objective of this study was to compare outcomes in EC patients undergoing either regimen, followed by surgery. Methods: We reviewed a prospectively collected database of EC patients undergoing esophagectomy following nCT or nCRT (1989-2013). Choice of therapy was at the discretion of the multidisciplinary team. Demographic data, clinical and pathologic staging, and survival (KM) were compared. Results: From 600 patients, 261 patients were identified with EC treated with nCRT (n=63) or nCT (n=199) followed by surgery. Patients were well matched for age, gender, PS, histology, and clinical stage. Following therapy, more nCRT patients had a complete clinical response (36% vs. 14%, p<0.001) by post-induction endoscopy and CT/PET. At surgery, 88% and 92% of CRT and CT patients underwent transthoracic esophagectomy. nCRT, in comparison to nCT, was associated with similar rates of cardiovascular (23% vs. 28%, p=0.43), pulmonary (24% vs. 25%, p=0.95), and infectious (13% vs. 9%, p=0.38) postoperative complications, and higher anastomotic leaks (23% vs. 14%, p=0.09). Perioperative (6% vs. 2%, p=0.06) and 90-day (11% vs. 4%, p=0.03) mortality was higher in nCRT than nCT patients. Following nCRT, 30% of patients had complete pathologic response vs. 6% of nCT patients (p<0.01). nCRT patients were more often node negative on final pathology (62% vs. 33%, p<0.001). Despite improved pathologic downstaging, nCRT patients had no improvement in 3-year disease-free (33% vs. 39%, p=0.84) or overall (54% vs. 52%, p=0.36) survival. No benefit of nCRT vs. nCT was apparent in 3-year overall survival in either adenocarcinoma (52% vs. 47%, p=0.25) or squamous cell carcinoma (44% vs. 61%, p=0.51). Conclusions: For patients undergoing surgery for EC, nCRT leads to increased local tumor response compared to nCT alone. However, nCRT is associated with increased early mortality and did not translate to improved long-term survival.