No clinically available biomarkers can predict pathological complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) with neoadjuvant chemoradiotherapy (nCRT). Considering that antitumor immunity status is an important determinant for nCRT, we performed an integrative analysis of immune-related gene profiles from pretreatment biopsies and constructed the first individualized immune signature for pCR and outcome prediction of ESCCs through a multicenter analysis. During the discovery phase, 14 differentially expressed immune-related genes (DEIGs) with greater than a twofold change between pCRs and less than pCRs (<pCRs) were revealed from 28 pretreatment tumors in a Guangzhou cohort using microarray data. Ten DEIGs were verified by qPCR from 30 cases in a Beijing discovery cohort. Then, a four-gene-based immune signature (SERPINE1, MMP12, PLAUR, and EPS8) was built based on the verified DEIGs from 71 cases in a Beijing training cohort, and achieved a high accuracy with an area under the receiver operating characteristic curve (AUC) of 0.970. The signature was further validated in an internal validation cohort and an integrated external cohort (Zhengzhou and Anyang cohorts) with AUCs of 0.890 and 0.859, respectively. Importantly, a multivariate analysis showed that the signature was the only independent predictor for pCR. In addition, patients with high predictive scores showed significantly longer overall and relapse-free survival across multiple centers (P < 0.05). This is the first, validated, and clinically applicable individualized immune signature of pCR and outcome prediction for ESCCs with nCRT. Further prospective validation may facilitate the combination of nCRT and immunotherapy.