Type I interferons are important in regulating immune responses to pathogens and tumors. All interferons are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as interferon-beta (IFN-beta) can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN-beta can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner, and we provide the structural basis of the IFNAR1-IFN-beta interaction. The IFNAR1-IFN-beta complex transduced signals that modulated expression of a distinct set of genes independently of Jak-STAT pathways. Lipopolysaccharide-induced sepsis was ameliorated in Ifnar1(-/-) mice but not Ifnar2(-/-) mice, suggesting that IFNAR1-IFN-beta signaling is pathologically relevant. Thus, we provide a molecular basis for understanding specific functions of IFN-beta.