Viral infection is the primary cause of respiratory morbidity in cystic fibrosis (CF) infants. Here, we identify that host factors allow increased virus replication and cytokine production, providing a mechanism for understanding the severity of virus disease in CF. Increased virus is due to lack of nitric oxide synthase 2 (NOS2) and 2′, 5′ oligoadenylate synthetase (OAS) 1 induction in response to virus or IFNγ. This can be attributed to impairment of activation of signal transducer and activator of transcription (STAT)1, a fundamental component to antiviral defense. NO donor or NOS2 overexpression provides protection from virus infection in CF, suggesting that NO is sufficient for antiviral host defense in the human airway and is one strategy for antiviral therapy in CF children.