Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in <i>IFIH1,</i> which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants <i>IFIH1</i> alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that <i>IFIH1</i> deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.