We have previously shown that hepatitis B virus (HBV) replication is inhibited noncytopathically in the livers of transgenic mice following injection of HBV-specific cytotoxic T lymphocytes (CTLs) or infection with unrelated hepatotropic viruses, including lymphocytic choriomeningitis virus (LCMV) and adenovirus. These effects are mediated by gamma interferon (IFNγ), tumor necrosis factor alpha (TNFα), and IFNα/β. In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFNγ (IFNγKO), the TNFα receptor (TNFαRKO), or the IFNα/β receptor (IFNα/βRKO) in order to determine the relative contribution of each cytokine to the antiviral effects observed in each of these systems. Interestingly, we showed that HBV replicates in unmanipulated IFNγKO and IFNα/βRKO mice at levels higher than those observed in control mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. We also showed that IFNγ mediates most of the antiviral effect of the CTLs while IFNα/β is primarily responsible for the early inhibitory effect of LCMV and adenovirus on HBV replication. In addition, we showed that the hepatic induction of IFNα/β observed after injection of poly(I · C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFNα. We also compared the relative sensitivity of LCMV and adenovirus to control by IFNγ, TNFα, or IFNα/β in these animals. Importantly, IFNα/βRKO mice, and to a lesser extent IFNγKO mice, showed higher hepatic levels of LCMV RNA and adenovirus DNA and RNA than control mice, underscoring the importance of both interferons in controlling these other viral infections as well.