SARS is a new human infectious disease with significant morbidity and mortality. A novel coronavirus (CoV) has been identified as the agent responsible. Interferon (IFN)-alpha's exhibit a critical role in host resistance to viral infection and in vitro experiments show that IFNs inhibit the SARS-CoV. IFN alfacon-1 is a synthetic IFN-alpha shown to be more potent than other type 1 IFNs. A pilot study was conducted in our laboratory to evaluate the potential clinical benefit and safety of IFN alfacon-1 in SARS treatment. Clinical results suggest that use of IFN alfacon-1 improved disease outcomes. To understand the role of IFN alfacon-1 against the SARS-CoV we studied gene expression profiles in the PBMC of SARS patients. We observe IFN-specific regulated gene expression, possibly associated with reduced viral load, and improved disease outcomes. In parallel, using the mouse CoV, MHV-1, we provide insights into IFN-activated signaling pathways that confer antiviral activity.