Oral adefovir dipivoxil (ADV) reduced viral load in transgenic mice expressing hepatitis B virus (HBV). Liver HBV DNA was reduced to <0.1 pg of viral DNA per microg of total DNA (pg/microg) following oral ADV therapy at a dosage of 100 mg/kg/day twice daily for 10 days as compared to a mean of 3.0 pg/microg for the placebo control group. Oral ADV treatment also reduced serum HBV DNA to 3.5 log10 genomic equivalents (ge)/ml compared to 5.3 log10 ge/ml for the placebo control group. With once daily treatments, ADV antiviral activity reached near maximum viral reduction by day 10 in the liver and reached an endpoint of liver virus inhibition at 1.0 mg/kg/day. The minimum effective dose was less than 0.1 mg/kg/day using inhibition of serum virus. Lamivudine (3TC) given orally at 500 mg/kg/day using the same treatment schedule marginally reduced the serum HBV DNA by 4-fold, but did not significantly reduce HBV liver DNA. Serum titer reduction was also identified in untreated or placebo-treated animals, which may have been caused by the stress of pre-treatment bleeding and multiple oral gavage treatments. This trauma/placebo-effect may have masked the extent of viral reduction in the serum in ADV- and 3TC-treated animals. Liver HBV RNA was not reduced by oral ADV treatments. The lack of RNA reduction was expected, because the HBV transgene is stably integrated into the chromosome and ADV inhibits polymerase activity after transcription of pregenomic RNA. ADV was identified to have potent anti-HBV activity in this HBV transgenic mouse model and could serve as a suitable positive control for future drug discovery experiments.