Activation of early response genes by interferons (IFNs) requires tyrosine phosphorylation of STAT (signal transducers and activators of transcription) proteins. It was found that the serine-threonine kinase mitogen-activated protein kinase (MAPK) [specifically, the 42-kilodalton MAPK or extracellular signal-regulated kinase 2 (ERK2)] interacted with the α subunit of IFN-α/β receptor in vitro and in vivo. Treatment of cells with IFN-β induced tyrosine phosphorylation and activation of MAPK and caused MAPK and Stat1α to coimmunoprecipitate. Furthermore, expression of dominant negative MAPK inhibited IFN-β-induced transcription. Therefore, MAPK appears to regulate IFN-α and IFN-β activation of early response genes by modifying the Jak-STAT signaling cascade.