We describe the case of a 77-year-old woman with chronic hepatitis C and well compensated cirrhosis in whom a single encapsulated 5.5 cm hepatocellular carcinoma was found in the right liver lobe. The patient was symptomatic with left upper quadrant pain and had elevated alfa-fetoprotein levels (3133 ng/ml). While she was waiting for liver resection and 2 months after the initial diagnosis the pain improved and alfa-fetoprotein levels normalized. A computerized tomography scan showed reduction in size of the lesion to 2.5 cm, with no central arterial enhancement, but with the demonstration of a peripheral rim enhancing in all dynamic phases. Follow up computerized tomography and magnetic resonance imaging examinations showed further reduction in size of the lesion to 1.3 cm with persistence of the enhancing rim 20 months after the initial diagnosis. The spontaneous and durable regression of the HCC and the persistent peripheral enhancing rim could be explained by a strong and persistent activation of the immune system directed against the neoplastic cells.