Importance: For patients with locally advanced esophageal squamous cell carcinoma, neoadjuvant chemoradiation has been shown to improve long-term outcomes, but the treatment response varies among patients. Accurate pretreatment prediction of response remains an urgent need., Objective: To determine whether peritumoral radiomics features derived from baseline computed tomography images could provide valuable information about neoadjuvant chemoradiation response and enhance the ability of intratumoral radiomics to estimate pathological complete response., Design, Setting, and Participants: A total of 231 patients with esophageal squamous cell carcinoma, who underwent baseline contrast-enhanced computed tomography and received neoadjuvant chemoradiation followed by surgery at 2 institutions in China, were consecutively included. This diagnostic study used single-institution data between April 2007 and December 2018 to extract radiomics features from intratumoral and peritumoral regions and established intratumoral, peritumoral, and combined radiomics models using different classifiers. External validation was conducted using independent data collected from another hospital during the same period. Radiogenomics analysis using gene expression profile was done in a subgroup of the training set for pathophysiological explanation. Data were analyzed from June to December 2019., Exposures: Computed tomography-based radiomics., Main Outcomes and Measures: The discriminative performances of radiomics models were measured by area under the receiver operating characteristic curve., Results: Among the 231 patients included (192 men [83.1%]; mean [SD] age, 59.8 [8.7] years), the optimal intratumoral and peritumoral radiomics models yielded similar areas under the receiver operating characteristic curve of 0.730 (95% CI, 0.609-0.850) and 0.734 (0.613-0.854), respectively. The combined model was composed of 7 intratumoral and 6 peritumoral features and achieved better discriminative performance, with an area under the receiver operating characteristic curve of 0.852 (95% CI, 0.753-0.951), accuracy of 84.3%, sensitivity of 90.3%, and specificity of 79.5% in the test set. Gene sets associated with the combined model mainly involved lymphocyte-mediated immunity. The association of peritumoral area with response identification might be partially attributed to type I interferon-related biological process., Conclusions and Relevance: A combination of peritumoral radiomics features appears to improve the predictive performance of intratumoral radiomics to estimate pathological complete response after neoadjuvant chemoradiation in patients with esophageal squamous cell carcinoma. This study underlines the significant application of peritumoral radiomics to assess treatment response in clinical practice.