In mouse cells carrying the dominant influenza resistance allele Mx+ (but not in Mx- cells) interferon-alpha/beta (IFN) induces an efficient antiviral state against influenza viruses and, concomitantly, the synthesis of a 75,000-Da protein (protein Mx). Here, indirect immunofluorescence using monoclonal antibodies was used to demonstrate that protein Mx accumulates in the nucleus of IFN-treated Mx+ cells, suggesting a nuclear site of action. Protein Mx is present in the nucleus of untreated influenza virus-resistant macrophages freshly explanted from the peritoneal cavity of Mx+ mice but is lost with time in culture when peritoneal macrophages become permissive for influenza virus.