We previously showed that an intraperitoneal infection with mouse hepatitis virus (MHV) resulted in acute hepatic failure accompanying extremely elevated viral growth in the liver in interferon-γ-deficient BALB/c (BALB-GKO), but not C57BL/6 (B6-GKO) mice. To examine the basis of the strain difference against MHV infection in interferon-γ-deficient mice, viral replication in primary hepatocyte cultures from BALB/c and B6 mice with or without the IFN-γ gene was compared in vitro. The MHV replication in BALB/c hepatocytes with or without the IFN-γ gene was significantly higher than that in B6 hepatocytes with or without the IFN-γ gene, suggesting that there is a strain difference in MHV replication in hepatocytes. Since a significant difference in MHV replication in hepatocytes was not observed between wild type and IFN-γ-deficient mice of the same genetic background, the phenomenon is thought to be independent of IFN-γ. However, pretreatment of hepatocytes with recombinant mouse interferon-γ inhibited MHV replication in a dose-dependent fashion. The results are discussed with respect to the pathology of MHV infection in mice with or without the IFN-γ gene.