Chronic hepatitis B virus (HBV) carriers are at considerable risk of reactivation of HBV infection when undergoing chemotherapy or immunosuppressive therapy. Complications of HBV reactivation, including asymptomatic elevation of HBV DNA levels, acute hepatitis, acute liver failure, and delays or dose reductions in chemotherapy, are avoidable with appropriate prophylactic oral antiviral therapy. This article reviews evidence for and presents a grade A recommendation supporting primary prophylaxis among HBV carriers with lamivudine. The dose and duration of prophylaxis, risk of lamivudine resistance, and future directions of prophylactic therapy for HBV reactivation during chemotherapy are discussed. Recommendations are suggested based on expert opinion for prophylaxis with the combination of lamivudine plus adefovir or with entecavir as alternative antiviral strategies that substantially reduce or avoid the risk of HBV antiviral drug resistance.