Background: Evidence informing current guidelines advising postoperative chemotherapy following trimodality therapy for esophageal cancer are limited. Our objective was to identify patients with locally advanced esophageal adenocarcinoma treated with trimodality therapy who may benefit from adjuvant chemotherapy. Methods: A single institution retrospective study was performed in 308 patients with esophageal adenocarcinoma who underwent neoadjuvant chemoradiation followed by surgery between 1989-2012. Kaplan-Meier analysis compared postoperative survival by clinical response to trimodality therapy and the use of adjuvant chemotherapy. Cox proportional hazards regression models estimated the association of adjuvant chemotherapy with survival. Results: After trimodality treatment, 93 out of 308 patients(30%) received adjuvant chemotherapy. Partial response to trimodality treatment was observed in 150(48%) patients; 50 of whom received adjuvant therapy. The median survival for partial responders who received adjuvant therapy vs. those receiving trimodality therapy alone was 53.2 vs. 27.6 months, respectively (p=0.047). Patients with complete response or no response to trimodality therapy showed no difference in median survival with the addition of adjuvant chemotherapy. Univariate Cox regression revealed a 26% decrease in relative hazard for long-term survival amongst patients who received adjuvant chemotherapy compared to no adjuvant therapy (HR=0.74, 95% CI 0.55-0.98). This association remained stable after adjusting for clinical response to trimodality therapy, age, and ASA score (aHR=0.75, 95% CI 0.55-1.01). Conclusions: Adjuvant therapy for patients with locally advanced esophageal adenocarcinoma was associated with a 26% decrease in relative hazard for mortality compared to trimodality treatment alone. Long-term survival following adjuvant therapy was dependent on initial response to trimodality therapy. Partial responders may benefit most from adjuvant chemotherapy.