Famciclovir is a novel guanosine nucleoside analogue with activity against herpes viruses and hepatitis B virus (HBV). Several preliminary reports have described efficacy of famciclovir in patients with recurrent hepatitis B after orthotopic liver transplantation (OLT). This report describes the largest study to date of long-term famciclovir treatment in patients with de novo or recurrent hepatitis B post-OLT. One hundred thirty patients with detectable serum HBV DNA after OLT received oral famciclovir 500 mg tid on a compassionate-use basis. Safety analyses included all treated patients; efficacy was assessed in all patients and a subgroup of 73 patients with complete baseline HBV DNA and alanine aminotransferase (ALT) data who had received > or =6 months of treatment. Efficacy parameters included serum levels of HBV DNA, ALT, and anti-HBe or anti-HBs seroconversion rates. Of the 70 patients treated for > or =6 months who could be evaluated for response/non-response to famciclovir, 52 (74%) were responders, defined as patients who experienced a 70% decrease or more in HBV DNA levels from baseline, or who became HBV DNA-negative, for at least two consecutive visits. In famciclovir responders, HBV DNA levels decreased by a median of 91% after 12 weeks of treatment, 95% after 6 months and >99% after 18 months of treatment. Marked differentiation between responders and non-responders could be made soon after the onset of treatment. Among anti-HBe positive patients with evidence of HBV replication, 12/13 were responders. Patients with high baseline ALT levels experienced more rapid suppression of HBV DNA during therapy with famciclovir. Famciclovir therapy was safe and well tolerated; serious adverse events were reported infrequently. Famciclovir treatment may be beneficial in patients with hepatitis B infection post-OLT.