Background: The impact of radiotherapy on the survival of patients with locally advanced esophageal cancer (EC) is presently insufficiently explored. Thus, using data from the Surveillance, Epidemiology, and End Results (SEER) Registry, this study aimed to compare the survival rates of patients with lymph node (LN) positive EC who received curative resection and were treated by neoadjuvant and adjuvant radiotherapy (RT), respectively. Methods: Retrospectively collected data from the SEER database using all 18 SEER registries on patients that underwent esophagectomy for EC was evaluated. All patients with LN positive pathology who received either neoadjuvant or adjuvant RT and curative intent esophagectomy from 2004 to 2007 were included. A comparison of 5-year relative survival outcome among groups categorized by sex, race, age, histology, and tumor size was performed. Results: A total of 933 patients were evaluated; 636 (69%) and 297 (31%) received RT in neoadjuvant and adjuvant setting respectively. Their overall 5-year relative survival rates were 32.8% (95% CI: 28.7-36.9) and 26.5% (95% CI: 21-32.3) (P=0.058). Patients in the neoadjuvant RT group who underwent curative resection for squamous cell carcinoma (SCC) of EC had an improved 5-year relative survival rate of 43.4% (95% CI: 32.5-53.8) compared to 26.5% (95% CI: 15.4-38.9) measured for the adjuvant RT group (P=0.03). The results further revealed a significant increase in the 5-year relative survival rates for stage T3 and Tx when RT was given in neoadjuvant setting compared to adjuvant RT group (T3 28.5% vs. 20.2%, P=0.011; Tx 46.3% vs. 8.9%, P=0.021). When the patients were grouped according to race, sex or age, or based on the timing of radiation relative to surgery, in the other histological or T stage groups, there were no statistically significant differences in the 5-year survival rates. Conclusions: Compared to adjuvant radiotherapy, neoadjuvant radiotherapy results in a better 5-year relative survival in patients with squamous cell neoplasms and/or T3, Tx stage disease.