Liver transplantation in patients with detectable hepatitis B virus (HBV) DNA is associated with a high rate of HBV recurrence and detectable HBV DNA is often considered a contraindication for liver transplantation. Famciclovir, an oral form of the purine nucleoside penciclovir, has been shown to inhibit HBV replication. This pilot study was conducted to determine whether a 6-month course of famciclovir, administered before transplantation, was effective in inhibiting HBV replication in patients with end-stage liver disease caused by HBV and detectable HBV DNA and to assess the posttransplant clinical and virologic outcome of patients becoming HBV DNA negative with famciclovir prior to transplantation. All eight patients enrolled were hepatitis B surface antigen (HBsAg) positive; their HBV DNA levels at baseline ranged from 4.3 to 25,321 pg/ml (mean 3,661 pg/ml). Six of the eight patients were also seropositive for HBeAg. An initial decline in HBV DNA titers occurred in all patients; however, only 25% (two of eight) of the patients became HBV DNA negative before transplantation and underwent liver transplantation. Seroconversion to hepatitis B surface antibody (HBsAb) (and HBeAb in HBeAg-positive patient) was demonstrated at the conclusion of famciclovir in the transplanted patients. Both patients remain HBV DNA negative at nearly 2 years of follow-up after transplantation. HBV DNA remained detectable in 63% (five of eight) of the patients. The mean HBV DNA level for patients who became HBV DNA negative was 5.1 pg/ml versus 424 pg/ml in nonresponders. Adverse effects attributable to famciclovir were not observed in any of the patients. Future studies should assess the predictors of response to famciclovir so that patients likely to achieve good virologic outcome can be targeted for such a therapy.