© Journal of Gastrointestinal Oncology. All rights reserved. Background: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) predict for survival in cancer patients. In patients receiving multimodality therapy, the effect of therapy on the NLR and PLR is not well understood. We evaluated changes in NLR and PLR among locally advanced esophageal cancer patients who received trimodality therapy. Methods: We performed a retrospective analysis of nonmetastatic patients with esophageal cancer who received neoadjuvant chemoradiation therapy (CRT) followed by esophagectomy at our institution between March 2000 and April 2012. NLR and PLR values were obtained for the following time points (TPs): (I) at diagnosis before CRT; (II) after CRT but prior to surgery; and (III) after surgery. We evaluated changes in NLR and PLR using the difference and ratio between TPs. Overall survival (OS) was evaluated by Kaplan-Meier analysis. Univariate and multivariate Cox regression models were applied to evaluate the independent prognostic significance of NLR and PLR. Results: This IRB-approved study included the records of 83 consecutive patients with stage II-IV esophageal cancer. The median age was 60 years, and median follow-up was 29.3 months. Patients were treated to a median prescription dose of 50.4 Gy (range, 50.4-56.4 Gy) in 28-33 fractions. Median NLR and PLR were 3.3 and 157.2, 12 and 645, and 11.5 and 391.7 at TPs 1, 2, and 3, respectively. On multivariate analysis, superior OS was associated with PLR ≥250 at TP3 (P=0.03), PLR decrease ≥609.2 between TP2 and TP3 (P=0.02), and PLR ratio (TP3/TP1) ≥1.08 (P=0.03). Inferior progression-free survival (PFS) was associated with NLR ≥36 at TP2 (P=0.0008), NLR increase ≥28.3 between TP1 and TP2 (P=0.0005), and PLR ratio (TP2/TP3) ≥0.38 (P=0.1). Pathologic complete response (PCR) was less likely for adenocarcinoma (AC) histology (P=0.03), NLR =10.6 at TP2 (P=0.04), and NLR increase ≥4.6 from TP1 to TP2 (P=0.03). Conclusions: To our knowledge, this is the first study to examine NLR and PLR values at various time intervals throughout treatment and demonstrate a correlation between OS, PFS, and PCR in patients undergoing trimodality therapy for esophageal cancer.