Valoctocogene roxaparvovec is the only factor VIII (FVIII) gene therapy currently approved for adults with severe hemophilia A in Europe and the USA. Elevated alanine transaminase (transaminitis) has been the most common adverse event observed during valoctocogene roxaparvovec clinical trials. Typically mild and transient, this marker of hepatocyte injury coincides, in some patients, with reduced FVIII levels and is generally managed with a reactive course of corticosteroids. An essential step in optimizing outcomes for patients who receive valoctocogene roxaparvovec is to review the extensive evidence currently available on this topic to determine practices for managing transaminitis, if it occurs. This forum article provides practical guidance based on the available clinical data and expert opinion for evaluating and managing transaminitis with corticosteroids to mitigate potential declines in FVIII activity levels in adults with severe hemophilia A who have received valoctocogene roxaparvovec.