Foscarnet (PFA), a viral DNA polymerase inhibitor, is a clinical agent for herpes viruses. The goal of the study was to evaluate the therapeutic efficacy of PFA in hepatitis B virus (HBV) infection. Intravenous infusion of PFA (1 g/day) for 4 weeks significantly reduced serum HBeAg (p<0.01) and HBV DNA copies (p<0.05) in 31 patients who were diagnosed with active chronic HBV infection (CHB) and had not received antiviral treatment previously. Alanine aminotransaminase (ALT), aspartate aminotransaminase (AST) and gamma glutamyl transpeptidase (gamma-GT) of the patients declined (p<0.001, 0.001 and 0.01, respectively). Kidney function (blood creatinine and urea nitrogen) remained unchanged. Another 21 lamivudine-resistant CHB patients with mutations at the tyrosine-methionine-aspartate-aspartate motif (YMDD) displayed a response to PFA similar to that mentioned above, with reductions in HBeAg (p<0.05), HBV DNA (p<0.01) and liver enzymes (ALT and AST, p<0.001; gamma-GT, p<0.05). Moreover, PFA reduced serum HBeAg (p<0.01), HBV DNA (P<0.05), AST (p<0.05) and ALT (p<0.02) in a cohort of 13 severe CHB patients with advanced liver damage. PFA was also evaluated in vitro and in vivo. PFA inhibited HBV DNA replication in HBV-transfected human HepG2 cells (2.2.15 cells) with reduced amount of HBV RC-DNA and DS-DNA. In the duck HBV-infected ducklings, PFA reduced viral DNA and duck HBsAg in the serum (p<0.01 for both).