The MyD88 adaptor protein is critical in Toll-like receptor and interleukin 1 receptor (IL-1R) signaling, but has not been linked to interferon-γ receptor (IFN-γR) signaling. Here we demonstrate that MyD88 increased the half-life but not the synthesis of IFN-γ-induced mRNA transcripts encoding tumor necrosis factor and IFN-γ-inducible protein 10. IFN-γ stimulation triggered a physical association between the IFN-γR1 and MyD88. Transcript stabilization required activation of mixed-lineage kinase 3 and p38 mitogen-activated protein kinase and the presence of an adenine-uridine–rich element in the transcript's 3′ untranslated region. These results demonstrate a MyD88-dependent post-transcriptional mechanism through which IFN-γ can enhance the expression of genes encoding proinflammatory molecules.