Considerable numbers of patients with chronic HBV infection follow a benign course, and HBV infection is detected in many patients as a chance finding. Even, patients with chronic hepatitis B exhibit periodic exacerbation and remission of hepatitis. Usually, acute flare or hepatitis is not so common in these patients. However, some chronic HBV carriers exhibit acute flare of hepatitis that may cause severe liver failure, a condition regarded as ACLF. ACLF in patients with chronic HBV infection may be caused by an activation of HBV or these may be due to several other causes. Superinfection with other hepatotrophic viruses and drugs may cause onset of ACLF. A role of host immunity is highly predicted in the pathogenesis of HBV-related ACLF. Many immunocytes including dendritic cells and inflammatory cytokines may have a role in the induction and pathogenesis of ACLF. Role of liver support system in the management of these patients have been highlighted.