Macrophages are the primary lung phagocyte and are instrumental in maintenance of a sterile, non-inflamed microenvironment. IFNs are produced in response to bacterial and viral infection and activate the macrophage to efficiently counteract and remove pathogenic invaders. Respiratory syncytial virus (RSV) inhibits IFN-mediated signaling mechanisms in epithelial cells; however, the effects on IFN signaling in the macrophage are currently unknown. We investigated the effect RSV infection had on IFN-mediated signaling in macrophages. RSV infection inhibited IFN- and IFN-activated transcriptional mechanisms in primary alveolar macrophages and macrophage cell lines, including the transactivation of important Nod-like receptor (NLR) family genes Nod1 and C2ta. RSV inhibited IFN- and IFN-mediated transcriptional activation by two distinct mechanisms. RSV impaired IFN-mediated STAT1 phosphorylation through a mechanism that involves inhibition of Tyk2 phosphorylation. In contrast, RSV-impaired transcriptional activation following IFN stimulation resulted from a reduction in the nuclear STAT1 interaction with the transcriptional co-activator CBP and was correlated with increased phosphorylation of STAT1, a dominant-negative STAT1 splice-variant, in response to IFN. In support of this concept, overexpression of STAT1 was sufficient to repress the IFN-mediated expression of C2ta. These results demonstrate that RSV inhibits IFN-mediated transcriptional activation in macrophages and suggests that paramyxoviruses modulate an important regulatory mechanism that is critical in linking innate and adaptive immune mechanisms following infection.