This study analyzed the retrospective data of 746 patients with esophageal cancer treated with photons (n = 500) and protons (n = 246) to determine the pretreatment clinical and radiation dosimetric risk factors of grade 4 radiation-induced lymphopenia (G4RIL). This study found that baseline absolute lymphocyte count and volumes of lung and spleen receiving ≥ 15 and ≥ 5 Gy, were the most important G4RIL risk determinants. The G4RIL risk for an average patient receiving protons increased by 19% had the patient switched to photons.