Hepatitis B virus (HBV) is an important cause of acute liver failure (ALF) worldwide. Two clinical entities are responsible for HBV-related ALF: acute hepatitis B and acute exacerbation of chronic HBV infection. Differentiation between these clinical entities is sometimes difficult, especially when past status of hepatitis B surface antigen (HBsAg) is unknown. A quantitative analysis of serum immunoglobulin M (IgM) antibody to the hepatitis core antigen (anti-HBc) may be helpful in the differential diagnosis. The recent definition of ALF in chronic HBV infection is somewhat problematic, because clinical, laboratory and radiological findings cannot reliably predict the presence of underlying liver cirrhosis in patients with acute exacerbation of chronic HBV infection. Explant liver shows underlying liver cirrhosis in >50% of these cases, even when there is no clinical evidence of liver cirrhosis. Therefore, it is advisable to exclude these patients in clinical trials because of the high incidence of underlying liver cirrhosis. The clinical course, however, is not different and neurologic complications are responsible for about half of the deaths, so a priority for liver transplantation should be maintained in these patients. The prognosis of HBV-related ALF is quite grim without liver transplantation with transplant-free survival rates ranging from 26% to 53%. To date, there is not enough evidence that antiviral therapy or artificial liver support devices can enhance the patient's survival, therefore, liver transplantation is still the only effective treatment option that can alter the grave prognosis of HBV-related ALF.