We defined the normal and innate (without functional B or T cells) inflammatory response to infection with mouse cytomegalovirus (MCMV) or herpes simplex virus (HSV). Intraperitoneal infection with MCMV or HSV induced an inflammatory infiltrate consisting largely of macrophages (Mφ) in both normal CB17 and severe combined immunodeficient (SCID) mice (lacking functional B or T cells). Mφ from infected mice were activated as shown by (i) spread morphology, (ii) increased expression of major histocompatibility complex (MHC) class II, MHC class I, and intercellular adhesion molecule-I molecules, and (iii) downregulation of Mφ-specific cell surface protein F4/80. In vivo administration of neutralizing antibodies specific for gamma interferon (IFNγ) or tumor necrosis factor alpha (TNFα) inhibited MHC class II induction on infiltrating in both normal and CB17 SCID mice. Anti-TNFα decreased the number of Mφ in virus-induced inflammatory exudates. The MCMV titer increased in the spleen and liver of IFNγ-depleted SCID mice, while TNFα depletion increased only splenic titers. MCMV-induced pathology was also increased in spleens of IFNγ- and TNFα-depleted SCID mice. We conclude that (i) Mφ activation is a prominent part of inflammatory responses to herpesvirus infection and (ii) IFNγ and TNFα play a critical role in both virus-induced Mφ activation and control of herpesvirus growth independent of T and B cells. This suggests that IFNγ- and TNFα-mediated Mφ activation is an important aspect of innate immunity to viral infection. As the Mφ may be involved in MCMV latency, IFNγ- and TNFα-dependent Mφ activation during primary infection may be relevant to establishment of viral latency.