A 51-year-old man who was hepatitis B surface antigen (HBsAg)-negative and positive for anti-hepatitis B surface antigen (anti-HBs) and anti-hepatitis B core antigen (anti-HBc), during rituximab therapy for chronic Lymphocytic leukemia, developed reactivation of hepatitis B virus (HBV) infection with hepatitis that proceeded towards hepatic failure and death in spite of lamivudine therapy. HBsAg remained persistently negative, notwithstanding a high HBV-DNA titer. Our observation, following other cases of fatal reactivation of HBV infection in patients receiving rituximab, suggests that, in all patients with previous markers of HBV infection, lamivudine prophylaxis should be considered during rituximab therapy.