A novel radiosensitization treatment involving the injection of hydrogen peroxide and sodium hyaluronate, using ultrasonic guidance, into a tumor immediately prior to intraoperative radiotherapy (IORT) was established for patients with stage IVa locally advanced unresectable pancreatic cancer. The aim of the present study was to assess the safety and efficacy of this novel treatment, termed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas-IORT (KORTUC and IORT). In total, 12 patients were treated with KORTUC-IORT, external-beam radiotherapy and systemic chemotherapy using gemcitabine hydrochloride and S-1. For evaluation of the therapeutic and adverse effects, contrast-enhanced computed tomography was conducted prior to the treatment, and one and six months following KORTUC-IORT. Medical examinations were performed every month at the regularly scheduled follow-up visits. The one- and two-year survival rates were 75 and 25%, respectively, and the median survival time was 16 months. All treatments associated with KORTUC-IORT were well-tolerated by the patients, with a small number of adverse effects and no serious complications. It was identified that the delivery of KORTUC-IORT is safe and effective, in combination with external-beam radiotherapy and systemic chemotherapy, for patients with locally advanced unresectable pancreatic cancer.