Background: Advanced hepatocellular carcinoma is a challenging disease to treat because of its late stage, rapid progression. We conducted a new treatment modality, meaning a cellular immune therapy based on personalized peptide vaccination (PPV-DC-CTL) combined with radiotherapy, to treat advanced hepatocellular carcinoma. It integrates personalized peptide vaccination in tumor immunotherapy, takes full advantages of the immune modulation of radiotherapy, promotes tumor cells releasing antigens and results in more effective therapeutic strategy in local control and system treatment. Methods: A total of 9 patients with advanced hepatocellular carcinoma were admitted. Multidisciplinary consultation confirmed that all the patients were clearly no surgical opportunity. 4 patients with multiple liver metastases (liver lesions > 3 pieces), 1 patient with liver metastases and portal vein tumor thrombosis, 1 patient with lung and bone metastasis, 2 patients with liver and lung metastasis, and 1 patients with liver metastases and peritoneal metastasis. Patients with metastasis were treated with precise radiotherapy combined with PPV-DC-CTL. Results: After radiotherapy and 1-3 cycles of PPV-DC-CTL treatment, AFP levels were significantly decreased in 6 patients, of which, imaging assessment of lesions researched PR for 3 patients and SD for another 3 patients. Response rate (RR) was 33%, and disease control rate (DCR) was 66%. This scheme is safe and well tolerated. None of the patients had side effects on liver and kidney function. Only one patient had Grade2 of bone marrow suppression, and the rest had no significant side effects on hemogram. Conclusions: Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced hepatocellular carcinoma, which is well tolerated, safe, feasible, and effective. Clinical trial information: ChiCTR-OIC-16010025.