AIM: Toll-like receptor 4 (TLR4) has been shown to be important for bacterial infection, especially to lipopolysaccharide signaling. Its possible role in HBV infection is studied in the present study.MATERIALS AND METHODS: pHBV3.6 plasmid,containing full-length HBV genome was used in the murine model of acute HBV expression by hydrodynamics in vito transfection. TLR4 normal or mutant mouse strain was compared to investigate the possible role of TLR4 in acute HBV expression.RESULTS: After pHBV3.6 injection, the infiltrating leukocytes expressed TLR4 were observed nearby the HBsAg-expressing hepatocytes. The HBV antigenemia as well as the replication and transcription were higher in TLR4-mutant C3H/HeJ mice than in normal C3H/HeN mice. The HBV-specific immune responses were impaired in the liver or spleen of the C3H/HeJ mice.Their inducible nitric oxide synthase (iNOS) expression on the hepatic infiltrating cells was also impaired. When adoptively transferring splenocy,tes from C3H/HeN mice to C3H/HeJ mice, the HBV replication was inhibited to the level as that of C3H/HeN.CONCLUSION: These results suggest that TLR4 plays an anti-HBV role in vivo through the induction of iNOS expression and HBV-specific immune responses after HBV expression.