Viral infection is associated with a vigorous inflammatory response characterized by cellular infiltration and release of the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α). In the present study, we identified a novel function of human cytomegalovirus (HCMV) that results in inhibition of IL-1 and TNF-α signaling pathways. The effect on these pathways was limited to cells infected with the virus, occurred at late times of infection, and was independent of cell type or virus strain. IL-1 and TNF-α signaling pathways converge at a point upstream of NF-αB activation and involve phosphorylation and degradation of the NF-κB inhibitory molecule IκBα. The HCMV inhibition of IL-1 and TNF-α pathways corresponded to a suppression of NF-κB activation. Analysis of IκBaα phosphorylation and degradation suggested that HCMV induced two independent blocks in NF-κB activation, which occurred upstream from the point of convergence of the IL-1 and TNF-α pathways. We believe that the ability of HCMV to inhibit these two major proinflammatory pathways reveals a critical aspect of HCMV biology, with possible importance for immune evasion, as well as establishment of infection in cell types persistently infected by this virus.