Despite hepatitis B immunoprophylaxis hepatitis B virus (HBV) recurrence is a frequent and often fatal complication after orthotopic liver transplantation (OLT). The purine nucleoside analogues penciclovir and its oral form famciclovir (FCV) proved to be well tolerated and effective against herpes simplex and zoster virus infections. In addition, an effective reduction of duck and human HBV replication was observed. Therefore, we conducted an uncontrolled pilot study of famciclovir in patients with HBV recurrence after OLT. Twelve patients have received famciclovir for at least 3 months in an open compassionate-use protocol. FCV was administered orally 500 mg three times a day for all patients (except one patient who was started on 750 mg three times a day for the first 2 weeks). Immediately after starting famciclovir, serum HBV DNA levels declined in 9 of 12 patients (75%) with a mean reduction from baseline levels of 80% after 3 months, 90% after 6 months, and > 95% after 12 months of treatment. With continued treatment, 5 of these 9 patients became negative by conventional hybridization assay, and in one of these HBV DNA became undetectable by polymerase chain reaction (PCR) 28 weeks after the start of treatment. Three patients showed no (sustained) reduction in HBV DNA after at least 3 months of treatment; therefore, FCV was stopped. Latest serum alanine aminotransferase (ALT) levels decreased in 6 of 12 patients (50%) with a median decrease of 80% (range, 40%-95%) in comparison to pretreatment ALT values. ALT levels normalized in 4 patients (33%). One patient died due to sepsis and peritonitis in week 13 of treatment. This event was not related to FCV. No clinically significant side effects were noticed in any patient. The oral nucleoside analog famciclovir reduces HBV replication and transaminase levels in patients with HBV recurrence after liver transplantation. Because long-term FCV treatment is well tolerated, famciclovir appears to be a promising antiviral strategy in the treatment of HBV in immunocompromised patients.