Background: Perineural invasion (PNI) is the process of neoplastic invasion of nerves. PNI has been reported as a prognostic indicator in malignancies of the pancreas, stomach, colon, rectum, prostate, head and neck, and biliary tract. However, studies examining the prognostic significance of PNI in esophageal cancer have shown inconsistent results. Analyses in patients with esophageal adenocarcinoma (EAC) have alternatively shown PNI to be a significant and a nonsignificant predictor of OS and DFS in both univariate and multivariate analysis. The majority of these studies analyzed patients who had not received any preoperative therapy. We sought to identify the prognostic significance of PNI in patients with EAC treated with neoadjuvant chemoradiotherapy (nCRT). Methods: We performed a retrospective analysis of 108 patients treated with nCRT and surgery for EAC at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute from 1996-2015. The final analysis identified 73 patients with data on PNI. We evaluated the association of PNI with disease-free survival (DFS), loco-regional progression-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) using log-rank and Cox proportional hazard modeling. Results: Of 73 patients, 17 patients (23%) had PNI and 56 patients (77%) did not have PNI at the time of surgery. The median follow-up was 15.3 months (range 5.8 to 179.3 months). The median DFS was 12.4 months for PNI+ and 36.4 months for PNI- (p = 0.042). The median LRFS was 48.2 months for PNI+ and median not reached for PNI- (p = 0.003). We did not detect a significant association between the presence of PNI and worse OS or DMFS. In a multivariate model including age, sex, gastric involvement, biopsy grade, presence of pathologic complete response, and pathologic N stage, PNI remained a significant independent predictor of LRFS (HR 0.37, 95% CI 0.14 to 1, p = 0.05). Conclusions: In patients with esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy, PNI discovered at the time of surgery is significantly associated with worse DFS and LRFS.