AbstractHepatitis B (HBV) reactivation (HBVr) is a potentially fatal complication in patients with past HBV exposure receiving immunosuppressive therapy. HBVr can occur in patients with chronic HBV infection as well as in patients with resolved HBV infection. In this article, we present the cases of four patients with resolved hepatitis B who presented with HBVr during or after immunosuppressive treatment, of whom two died as a consequence of HBVr. We then reflect on and summarize the recommendations of four major societies for the screening and management of previously HBV-exposed patients planned to receive immunosuppressive treatment. Current guidelines recommend screening for HBV in all patients planned to receive immunosuppressive therapy. Risk of HBVr is assessed based on the serological status of the patient and the planned immunosuppressive drug regimen. For patients considered to be at low risk of HBVr, management consists of serological monitoring for HBVr and immediate preemptive antiviral therapy in the case of HBVr. For patients considered to be at intermediate or high risk for HBVr, antiviral prophylaxis should be initiated concordantly with the immunosuppressive therapy and continued for up to 18 months after cessation of the immunosuppressive regimen. Areas of uncertainty include the risk of novel and emerging immunosuppressive and immune modulatory drugs and the exact duration of antiviral prophylaxis. Greater awareness is needed among clinicians regarding the risk of HBVr in patients receiving immunosuppressive therapy, especially in low-endemicity settings. Implementation of screening and management programs and decision support tools based on the presented guidelines may improve the management of these patients.