Definitive chemoradiotherapy is the standard treatment for unresectable, locally advanced esophageal cancer. However, radiotherapy (RT) often affects the immune system of patients. One of the possible mechanisms of lymphopenia after RT is that a large number of circulating lymphocytes in the systemic and pulmonary circulation will be killed by more sessions of low-dose radiation. The impact of dose-volume parameters of organs at risk (OARs) on absolute lymphocyte count (ALC) and the relationship between the extent of lymphocyte count reduction and survival prognosis in patients with middle and lower thoracic esophageal squamous cell carcinoma (ESCC) both remain difficult to determine.To determine the relationship between RT parameters, lymphocyte count and survival prognosis of esophageal cancer patients.The clinical data of 112 patients with stage I-III ESCC who received definitive RT were analyzed retrospectively. The ALC values before RT, weekly during RT, and within 1 month after RT were determined. Logistic regression was used to evaluate the correlation between the parameters of radiation OARs and the lowest point of the ALC. Kaplan-Meier and Cox regression analyses were used to evaluate the relationship between the lowest point of the ALC and patient survival during RT.The median value of the ALC before treatment was 1.57 × 109 cells/L, and 32 patients (28.6%) showed grade 4 ALC reduction during RT. The reduction in G4 ALC during RT was significantly associated with poor overall survival (OS) and progression-free survival. Multivariate analysis showed that stage III tumors (P = 0.003), high heart V10 (P = 0.046), high lung V5 (P = 0.048), and high lung V20 (P = 0.031) were associated with G4 ALC reduction during RT.The reduction in G4 ALC is related to OS. Joint evaluation of the tumor stage and dose volume parameters has predictive value for G4 ALC reduction and OS.©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.