Although liver disease seems to be stable in most patients who are infected with lamivudine-resistant mutant hepatitis B virus (HBV) in the short term, it may progress to more-advanced disease in some patients. In our pilot study, we investigated the efficacy of oral ganciclovir for the treatment of lamivudine-resistant HBV infection. Six patients infected with lamivudine-resistant HBV (3 patients had decompensated cirrhosis and 3 had chronic active hepatitis without cirrhosis) were included. Ganciclovir was administered at a dosage of 3 g daily for 6 months. Four of 6 patients completed the 6-month treatment period. Two patients with cirrhosis completed only 2 months of ganciclovir treatment because they died of cirrhosis complications. None of the patients had a > or =2-log(10) reduction of HBV DNA and complete alanine aminotransferase normalization at the end of their treatment regimens. In conclusion, 6 months of ganciclovir treatment is not effective for suppression of lamivudine-resistant HBV infection.