172 Background: Neoadjuvant chemotherapy (NAC) is the gold standard approach for locally advanced esophageal cancer (EC), however the addition of radiation remains largely controversial. We sought to investigate the role of neoadjuvant radiation in resectable EC by comparing outcomes of patients who underwent neoadjuvant chemotherapy with (NACR) or without radiation (NAC) using a large nationwide cohort. Methods: National Cancer Data Base (NCDB) was queried for patients with non-metastatic EC between 2010 and 2014. Kaplan-Meier, log-rank and Cox multivariable regression analysis were performed to calculate overall survival (OS). Logistic regression was used to identify factors associated with 90-day mortality and complete pathological response (pCR). Results: A total of 12,546 EC patients who underwent neoadjuvant therapy were included: the majority were males (84%), Caucasians (90.3%), and had adenocarcinoma (81.1%), cT3 (60.6%) and cN1 (49.1%). 11,269 (89.8%) patients had NACR, whereas 969 (7.7%), NAC alone. pCR rate was 14.1% (19.2%, NACR vs. 6.3%, NAC, p < 0.001). Neoadjuvant radiation was an independent predictor for improved pCR [HR 0.305, 95% CI 0.205-0.454, p < 0.001], however OS was similar in patients undergoing NAC with or without radiation (35.9 vs. 37.6 months, respectively, p = 0.393). This persisted regardless of tumor staging. There was a trend towards worse 90-day mortality after radiation (8.2%, NACR vs. 7.7%, NAC; HR 1.410, 95% CI 0.975-2.038, p = 0.068). In Cox regression, controlling for patient and disease-related factors, neoadjuvant radiation was an independent predictor of worse OS (HR 1.322, 965% CI 1.177-1.485, p < 0.001). Conclusions: This is the largest study comparing NACR versus NAC in resected EC. The addition of radiation to neoadjuvant chemotherapy is associated with improved pathological response rates, however it had deleterious effects in long-term and possibly, short-term survival. Our findings suggest that NAC without radiation may be the optimal neoadjuvant therapy in resectable EC, however further evidence with randomized clinical trials is warranted.