We expressed human type I interferon (IFN) receptors (IFNAR) in mice and investigated their signaling. Using a hydrodynamics-based delivery method, vectors containing the genes for IFNAR1 and IFNAR2 were transferred into mice. Six hours after gene-transfer, mice were intravenously injected with human IFN-alpha at 10,000 IU. IFNAR1 and IFNAR2 were both expressed in the liver, but not spleen or lung. The receptors were coexpressed in single liver cells. One hour after IFN-alpha injection, the phosphorylation status of signal transducer and activator of transcription factor 1 (STAT1), a key molecule of IFN signaling, was determined. Phosphotyrosine-STAT1 (p-STAT1), localized to the nucleus of IFNAR-expressing cells, was increased in the livers of IFNAR gene-transferred mice but not in control vector-transferred animals. In conclusion, functional human IFNAR can be delivered to the mouse liver, resulting in an increase in p-STAT1 levels following human IFN-alpha stimulation.