We investigated the effects of prophylactic nucleoside analogue treatment on HBV activation in patients with antibodies against core antigen (HBcAb+) patients undergoing immunosuppressive therapy. Patients (113), who were HBcAb+, with various autoimmune diseases, undergoing immunosuppressive therapy, were divided into two groups. The control group, not treated with antivirals, and the prophylactic group, treated with antiviral drugs. The two groups were evaluated for changes in serum biochemical marker (alanine aminotransferase ALT), virological marker (HBV DNA) and for seroconversion. In the control group, the number of patients with an increase in ALT in patients with isolated HBcAb and HBcAb and antibodies against HBsAg (HBsAb +) were five (20.0%) and one (2.8%), respectively (P < 0.05). There were six cases (24.0%) with an increase in HBV DNA in the isolated HBcAb+ subgroup and one case (2.8%) in HBsAb+/HBcAb+ subgroup (P < 0.05). In the HBcAb+ only population, six patients (24.0%) in the control group had an increase in HBV DNA compared with none in the antiviral prophylactic group (P < 0.05). One patient (4.0%) with HBcAb+ in the control group underwent an HBsAg seroconversion when receiving immunosuppressive therapy for 18 months, while none in the antiviral prophylactic group underwent reversion to HBsAg positivity (P = 0.4949). Under immunosuppressive condition, the risk of HBV activation was much higher in patients with HBcAb than in patients with both HBcAb and antibodies to HBsAb group. Antiviral prophylactic therapy could significantly reduce the risk of HBV reactivation.