Chemotherapy-induced hepatitis B virus (HBV) reactivation is a serious problem in chronic HBV carriers with hematologic malignancies. In 12 patients with hematologic malignancies, we performed a prospective study to determine the effectiveness of nucleoside analogues in the pre-emptive therapy of chemotherapy-induced HBV reactivation. HBV reactivation occurred in seven patients (58.3%) whereas five of the seven patients (71%) responded to nucleoside analogue therapy. HBV reactivation-related acute liver failure and death was not observed in the present study. All five patients with chronic lymphocytic leukemia (CLL) experienced chemotherapy-induced HBV reactivation regardless of the chemotherapy regimen. Therefore, we suggest that CLL carries a significant risk of chemotherapy-induced HBV reactivation. The pre-emptive therapy of chemotherapy-induced HBV reactivation appears to be safe, based on the results of this pilot study. Pre-emptive therapy enables the definition of high-risk patients who cannot be identified by primary prophylaxis.