We describe a case of hepatitis B virus (HBV) reactivation that responded to lamivudine therapy in a 58-year-old man with advanced hepatocellular carcinoma (HCC). After seroconversion of hepatitis B e antigen to e antibodies by interferon therapy, the patient was found to have HCC with a portal tumor thrombus. A transarterial port was placed in the right femoral artery to permit infusion of epirubicin and cisplatin. After 3 months of arterial chemotherapy, the serum alpha-fetoprotein level had decreased and tumor staining diminished. Laboratory examinations suggested a flare-up of hepatitis B. Lamivudine was given to manage HBV reactivation. After 1 month, the serum HBV DNA level fell below the detection limit, and the alanine aminotransferase activity decreased to the normal range. With further arterial chemotherapy for HCC, no tumor staining was detected on computed tomography. Administration of lamivudine decreased serum HBV DNA levels for 7 months. Our findings suggest that HBV may be reactivated during chemotherapy for HCC, similar to other types of malignancies, and that lamivudine is effective for the management of HBV reactivation.