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Viruses express a wide range of immune evasion proteins to modulate host immunity. The DNA-encoded poxvirus vaccinia virus (VACV) carries IFN-I inhibitors of which the viral IFN-I receptor B18 binds to the surface of host cells to compete with the endogenous host IFN-I receptor. Upon VACV infection WT mice survive infection with mild signs of disease, while IFN-I is not detectable in the serum. Surprisingly, IFN-I receptor deficient (IFNAR−/−) mice succumb to VACV infection within 5 days. Thus, we hypothesized that upon VACV infection local IFN-I responses were induced which significantly affected the disease course. To monitor local IFN-I responses, we infected IFN- β -luciferase reporter mice with VACV. By in vivo imaging we found that upon VACV infection local IFN- β responses were induced within secondary lymphoid organs. Studies with Mx2-luciferase reporter mice, which express luciferase upon IFNAR triggering, revealed significant IFNAR triggering within the liver and intermediate triggering in secondary lymphoid organs. Of note, viral titers in the liver of infected IFNAR−/− mice were increased when compared to WT mice. Additionally, VACV infected IFNAR−/− mice showed dramatically enhanced cytokine responses as well as elevated liver enzyme levels in the serum. Histological analysis of liver of VACV infected WT mice revealed that such mice developed mild hepatitis around day 5 post infection. In contrast, livers of infected IFNAR−/− mice showed signs of severe hepatitis, massive influx of lymphocytes and inflammatory islets including acute necrotic areas. VACV infection of macrophage-specific IFNAR−/− (LysM-Cre[wt/+]IFNARfl/fl) mice revealed that IFNAR signaling of macrophages was needed to protect mice from severe liver damage, whereas IFNAR signaling of hepatocytes (Alb-Cre[wt/+]IFNAR[fl/fl ]mice) was dispensable. Collectively our results indicated that locally induced IFN-I played a crucial role in balancing cytokine responses and were necessary to trigger macrophage-mediated liver protection.