Background: Neoadjuvant chemoradiation therapy (CRT) followed by esophagectomy is the current standard of care for patients with locally advanced esophageal cancer. The potential benefit of additional postoperative chemotherapy is still under investigation. In this study, we utilized the National Cancer Database to assess the effect of adjuvant chemotherapy in patients who were found to have node negative disease (pN0) following surgery. Methods: Patients with locally advanced esophageal cancer who received neoadjuvant CRT followed by esophagectomy from 2004 to 2014 were retrospectively identified using the National Cancer Database. Patients who were postoperatively staged as pN0 were then separated based on whether or not they received adjuvant chemotherapy. Using Kaplan-Meier estimation and a multivariate cox regression analysis, the overall survival of those who received adjuvant therapy was then compared to those who received neoadjuvant CRT alone. Results: 3,159 patients with locally advanced esophageal cancer underwent neoadjuvant CRT and were found to be pN0 following surgery. 119 of these patients received postoperative chemotherapy. The 1, 5, and 8-year overall survival in those receiving adjuvant therapy was 95.9%, 49.9%, and 47.7% compared to 85.8%, 44.6%, and 33.0% in those receiving neoadjuvant CRT alone, respectively (p = 0.019). Based on multivariate analysis, receiving adjuvant chemotherapy was independently associated with increased overall survival (p = 0.011; HR 0.658; 95% CI, 0.476 to 0.908). Conclusions: Adjuvant chemotherapy may improve survival in patients with locally advance esophageal cancer who have no evidence of local nodal metastases following surgery. Additional clinical trials are needed to further confirm which patients may benefit from adjuvant therapy and to determine the optimal postoperative therapeutic regimen.