Hepatitis B reactivation (HBVr) can occur due to a variety of immune-modulating exposures, including multiple drug classes and disease states. Antiviral prophylaxis can be effective in mitigating the risk of HBVr. In select cases, clinical monitoring without antiviral prophylaxis is sufficient for managing the risk of HBVr. This clinical practice guideline update aims to inform frontline health care practitioners by providing evidence-based practice recommendation for the management of HBVr in at-risk individuals.