Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations inIRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered lifethreatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from singlegene inborn errors of immunity.