Patients with severe exacerbation of chronic hepatitis B, sometimes developing into fulminant liver failure, are at high risk for mortality even with antiviral therapy. The efficacy of immunosuppressive therapy in clinically severe exacerbation of chronic hepatitis B has not been well demonstrated. In this study, we evaluated the efficacy of the early introduction of immunosuppressive therapy in combination with antiviral therapy in such patients. Forty-two patients, 29 men and 13 women, were defined as having severe exacerbation of chronic hepatitis B based on our uniform criteria, and were enrolled in this study. Sixteen patients between 1982 and 1996 were analyzed retrospectively. We defined the criteria of severe disease in 1997, and then began to introduce sufficient doses of corticosteroids prospectively. Nucleoside analogs were administered in combination with corticosteroids after 1999. Twenty-six patients between 1997 and 2007 were analyzed prospectively. In the retrospective study between 1982 and 1996, four of 16 (25%) patients recovered. In the prospective study between 1997 and 2007, 17 of 26 (65%) patients recovered; 15 of 17 patients treated with corticosteroids with or without antiviral drugs within 10 days after the diagnosis of severe disease recovered, none of five treated similarly but later than 10 days after the diagnosis recovered, and two of three treated with antiviral drugs recovered. The early introduction of sufficient doses of corticosteroids and nucleoside analogs could be one option for reversing the potential deterioration of patients with clinically severe, life-threatening exacerbation of chronic hepatitis B.