Single high-dose irradiation has become a safe and encouraging form of radiation therapy but variations in the histological changes after irradiation have not been fully understood in clinical settings. The aim of this study was to investigate the histological changes of tumor cells after single high-dose, direct irradiation with a case of cutaneous squamous cell carcinoma that developed on a burn scar. The patient received irradiation followed by radical resection of the tumor. Tissues before and after irradiation were stained with Hematoxylin and Eosin (H&E), TdT-mediated dUTP-X nick end labeling (TUNEL), and by immunohistochemistry for MIB-1, p53, and p21. Massive necrosis was noted after irradiation but a few viable tumor cells remained. Preradiation histology revealed MIB-1 and p53 as positive, and p21 tumor cells as partially positive. These expressions were reduced after irradiation. The TUNEL stain was consistently negative. It was established that tumor cell death after single high-dose irradiation was caused mainly by necrosis rather than apoptosis in clinical settings.