We report a case of acute fatal exacerbation of chronic hepatitis B in a 50-year-old man with multiple myeloma being treated with thalidomide. The patient had a medical history of chronic hepatitis B and was diagnosed with stage IIIA multiple myeloma. He suffered two episodes of transient transaminitis of unknown origin after successive autologous stem cell transplantations. Spontaneous resolutions of the transaminitis were observed without special management. At that time, PCR of hepatitis B virus (HBV) were all-negative. After 5-months' administration of thalidomide for the second relapse of the multiple myeloma, he suddenly experienced dizziness and jaundice. The level of HBV DNA was 1,641 pg/mL and the serologic tests for other viruses were negative. Despite conventional supportive care, he expired due to septic shock caused by Klebsiella pneumonia. Based on the stable disease status of the multiple myeloma and exclusion of other hepatotoxic agents, it was assumed that the exacerbation of the hepatitis B virus during the thalidomide therapy preceded the bacterial sepsis. With the increased use of thalidomide in cancer treatment, cautious monitoring of the viral burden should be performed in patients with chronic hepatitis B.