The aim of this study was to assess the relative prognostic value of biomarkers to measure the systemic inflammatory response (SIR) and potentially improve prognostic modeling in patients undergoing potentially curative surgery for esophageal adenocarcinoma (EC). Consecutive 330 patients undergoing surgery for EC between 2004 and 2018 within a regional UK cancer network were identified. Serum measurements of haemoglobin, C-reactive protein, albumin, modified Glasgow Prognostic Score (mGPS), and differential neutrophil to lymphocyte ratio (NLR) were obtained before surgery, and correlated with histopathological factors and outcomes. Primary outcome measures were disease-free (DFS) and overall survival (OS). Of 330 OC patients, 294 underwent potentially curative esophagectomy. Univariable DFS analysis revealed pT, pN, pTNM stage (all p < 0.001), poor differentiation (p = 0.001), vascular invasion (p < 0.001), R1 status (p < 0.001), perioperative chemotherapy (p = 0.009), CRP (p = 0.010), mGPS (p = 0.011), and NLR (p < 0.001), were all associated with poor survival. Multivariable Cox regression analysis of DFS revealed only NLR [Hazard Ratio (HR) 3.63, 95% Confidence Interval (CI) 2.11-6.24, p < 0.001] retained significance. Multivariable Cox regression analysis of OS revealed similar findings: NLR [HR 2.66, (95% CI 1.58-4.50), p < 0.001]. NLR is an important SIR prognostic biomarker associated with DFS and OS in EC.