Hepatocellular carcinoma accounts for 90% of primary liver cancers and represents a growing health problem worldwide. We report the complex case of a 71 year-old patient diagnosed with a large hepatocellular carcinoma and presenting an extensive vascular invasion of the middle hepatic vein and the inferior caval vein ascending to the right atrium with no extrahepatic spread. Due to several comorbidities, a systemic treatment by tyrosine kinase inhibitors was contraindicated. After discussion at the multidisciplinary hepatology tumor board, he was referred for selective internal radiation therapy. Unfortunately, the work-up showed an important lung shunt not allowing radioembolization. No clear recommendations are available in this situation. The decision was made to propose a combination treatment by transarterial chemoembolization, that was performed using a new generation of radio-opaque microspheres loaded with doxorubicin, followed by immunotherapy. This allowed a complete response with a very good quality of life.