Objective To investigate the predictive value of prognostic nutritional index (PNI) and cytotoxic T lymphocyte associated antigen 4 (CTLA⁃4) expression level in peripheral blood for postoperative recurrence of esophageal squamous cell carcinoma (ESCC) patients. Methods A total of 133 ESCC patients who underwent curative resection in People's Hospital of Tinghu District, Yancheng City and General Hospital of Eastern Theater Command from April 2014 to June 2018 were included, and the clinic pathological and follow⁃up data of all patients were retrospectively collected. Receiver operating characteristics (ROC) curve was used to determine the optimal cut⁃off point and predictive value of preoperative PNI and CTLA⁃4 expression level in peripheral blood for postoperative recurrence in ESCC patients. Kaplan⁃Meier curve was plotted to evaluate the impact of PNI and CTLA⁃4 expression level in peripheral blood on the recurrence⁃free survival (RFS) of ESCC patients. In addition, Cox multivariate regression analysis was performed to determine the independent predictors of postoperative recurrence and metastasis in ESCC patients. Results ROC curve indicated that the cut⁃off values of PNI and CTLA⁃4 expression in peripheral blood for predicting recurrence of ESCC patients were 48.2 and 0.410 ng/ml, respectively. The AUC values for PNI and CTLA⁃4 expression in peripheral blood were 0.666 (95%CI= 0.572-0.759) and 0.606 (95%CI=0.507-0.704), respectively. Based on the optimal cut⁃off point, high CTLA⁃4 expression in peripheral blood was significantly associated with histological grade (χ２ = 10.231, P=0.001) and T stage (χ２ = 5.198, P=0.023). Kaplan⁃Meier curve showed that ESCC patients with high CTLA⁃4 expression had a poorer RFS than those with low CTLA⁃4 expression (5⁃year RFS rate, 41.7% vs 61.2%), with a statistically significant difference (χ２= 3.919, P=0.047). On the other hand, the 5⁃year RFS of ESCC patients with preoperative PNI <48.2 was significantly worse than that of those with PNI ≥48.2 (39.6% vs 61.3%, χ２ = 6.362, P=0.016). Multivariate Cox regression analysis further confirmed the independent prognostic significance of PNI (HR=3.043, 95%CI=1.290-7.179, P=0.011) and CTLA⁃4 expression in peripheral blood (HR=2.250, 95%CI=1.286-3.938, P=0.004) in ESCC patients. In addition, ROC curve showed that the AUC value of PNI combined with CTLA⁃4 expression in peripheral blood for predicting recurrence in ESCC patients was 0.694 (95%CI= 0.604-0.7849), which was better than that of either PNI or CTLA⁃4 expression alone. Conclusion Combination of PNI and the expression level of CTLA⁃4 in peripheral blood further improved predictive performance of recurrence in ESCC patients, and it might be a sensitive indicator for prognostic assessment of ESCC patients.