Type I interferons (IFN-alpha and -beta) play a key role in anti-viral immunity, and we sought to define the molecular mechanisms by which the sympathetic nervous system (SNS) inhibits their effects. In peripheral blood leukocytes and plasmacytoid dendritic cells (pDC2), induction of interferon anti-viral activity by double-stranded RNA (poly-I:C) or CpG DNA was substantially inhibited by norepinephrine and by pharmacologic activation of the cAMP/PKA signaling pathway. This effect was specific to Type I interferons and driven by PKA-mediated repression of IFNA and IFNB gene transcription. Luciferase reporter analyses identified tandem interferon response factor-binding sites in positive regulatory domains I and III of the IFNB promoter as a key target of PKA inhibition. PKA suppression of Type I interferons was associated with impaired transcription of interferon response genes supporting the "anti-viral state", and was sufficient to account for norepinephrine-induced enhancement of HIV-1 replication. Given the ubiquitous role of Type I interferons in containing viral replication, PKA-mediated inhibition of IFN transcription could explain the stimulatory effects of catecholamines on a broad range of viral pathogens.