Background: The prognostic role of perineural invasion (PNI) in esophageal squamous cell carcinoma (ESCC) remains unclear. We aimed to assess the prognostic effects of PNI in resectable ESCC patients. Methods: We retrospectively examined the medical records of patients who underwent esophagectomy from January 2010 to December 2017 at Sichuan Cancer Hospital. Factors associated with PNI and the impact of PNI on prognosis and overall survival (OS) were analyzed. We also performed survive analysis associated with OS and disease-free survival (DFS). Results: The median follow-up period in this study was 36.7 months. PNI was present in 18.0% (404/2,247) of ESCC patients. PNI-positive was correlated with a shorter OS than PNI-negative (median OS: 31 vs. 58 months, P<0.001). And PNI-positive was also associated with shorter median DFS compared to those without PNI (median OS: 29 vs. 60 months, P<0.001). In lymphovascular invasion (LVI)-negative, pII/III stage, and pN0 subgroups, the OS of PNI-positive patients was generally decreased in different subgroups of patients. In the subgroup of PNI-positive patients, postoperative adjuvant therapy did not provide a survival benefit (median OS: 32 vs. 30 months, P=0.77). PNI was an independent prognostic factor (HR: 1.174, 95% CI: 1.003-1.373, P=0.046) in the multivariable survival analysis for DFS. Conclusions: PNI is a potential independent prognostic factor for ESCC patients. Further study is needed to determine whether postoperative adjuvant therapy is necessary for thoracic ESCC patients who have achieved R0 resection and PNI-positive.