Background <p>Neoadjuvant chemoradiotherapy (NCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). This study aims to explore the effect of the estimated dose of radiation to immune cells (EDRIC) on lymphocytes in patients with locally advanced ESCC undergoing NCRT and evaluate the impact of EDRIC on patient prognosis.</p> Methods <p>This retrospective study included patients with locally advanced ESCC who received NCRT followed by radical esophagectomy at our institution between March 2016 and December 2022. EDRIC was calculated as a function of the number of fractions and the average doses to the lungs, heart, and remaining body. The optimal cut-off value of EDRIC was determined based on disease-free survival (DFS), and patients were divided into two groups according to this cut-off value. Kaplan–Meier and Cox proportional hazards regression analyses were used to estimate overall survival (OS) and DFS.</p> Results <p>The 182 patients included in the study had a mean EDRIC of 5.41 ± 1.70&#xa0;Gy and an EDRIC cut-off value of 6.86&#xa0;Gy. Patients with an EDRIC ≤ 6.86&#xa0;Gy had a significant advantage in DFS (hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.20–0.68, <i>P</i> = 0.001) and OS (HR: 0.22, 95% CI: 0.10–0.48, <i>P</i> = 0.001). EDRIC was closely associated with the lymphocyte nadir (<i>P</i> &lt; 0.001) and lymphocytopenia values (<i>P</i> &lt; 0.001). Patients with a lymphocyte nadir ≤ 0.16 × 10⁹/L had poorer DFS (HR: 2.04, 95% CI: 1.07–3.88, <i>P</i> = 0.025) and OS (HR: 2.52, 95% CI: 1.14–5.56, <i>P</i> = 0.018).</p> Conclusion <p>EDRIC is an independent prognostic factor for patients with locally advanced ESCC undergoing NCRT. A higher EDRIC is associated with poorer DFS and OS and is closely related to reduced lymphocyte counts. As a quantifiable parameter, future research should explore methods of lowering EDRIC during NCRT while ensuring adequate tumor coverage and sufficient dosage.</p>