Acute exacerbation (AE) of chronic hepatitis B virus (HBV) infection in cancer chemotherapy patients and in organ transplant recipients receiving immunosuppressants may cause catastrophe and high mortality. Hence, immediate treatment with nucleoside analogues for such patients has become a consensus. Anti-HBV therapeutic trials in Asia have shown that AE of chronic hepatitis B (CH-B) may result in increased sustained remission (SR) rate with lamivudine monotherapy. Nonetheless, AE episodes in CH-B patients may evolve uneventfully and lead to spontaneous remission. Thus, the policy of immediate anti-HBV therapy for AE patients reaches an impasse. Once treatment is initiated, life long HBV suppression may be necessary. To determine whether lamivudine monotherapy during an AE of CH-B results in an increase in SR compared with no therapy. A cohort of 154 CH-B patients seropositive for hepatitis B e antigen with AE formed the study group. This included 102 cases receiving a nationwide therapeutic trial of 18-month lamivudine monotherapy that were compared with 52 cases with no therapy. All were observed for at least 30 months, which encompassed the 18-month on treatment period and a 12-month posttreatment follow-up. No significant increase was observed in the SR rate in the lamivudine treatment group compared with the spontaneous remission rate in the untreated patients (P=0.782, Fisher's exact test). AE does not increase the SR rate during 18-month lamivudine monotherapy. Immediate lamivudine therapy for AE patients is not justified as mandatory. The policy should be only applied to AE patients with impending liver failure.