Reactivation of hepatitis B virus (HBV) replication in hepatitis B surface antigen (HBsAg)-positive patients is associated with immunosuppressive therapy. However, the interactions between endogenous glucocorticoid in Cushing's syndrome and HBV-related hepatitis remain unclear. Here, we describe the management of a 32-year-old male HBV carrier with Cushing's syndrome caused by an adrenal cortical adenoma, who developed severe hepatitis B. Repeated episodes of septicemia resulting from hypercortisolemia-related immunosuppression further compromised his hepatic condition. Adrenalectomy could not be performed due to coagulopathy. Lamivudine was not available at that time in Taiwan, and this patient died of hepatic failure and sepsis. At autopsy, his liver showed submassive necrosis with small regenerative nodules. The hepatocytes were positive for HBsAg (membrane and cytoplasmic) and hepatitis B core antigen (nuclear and cytoplasmic). Screening for HBsAg is of crucial significance for immunocompromised individuals. Once positive HBsAg is detected in immunosuppressed patients, liver function and viral status should be closely monitored to enable earlier diagnosis and prompt treatment with the newer nucleoside analogues that actively fight HBV.