More than half a dozen poxvirus-encoded members of the serpin superfamily of serine proteinase inhibitors have been discovered, but only one of these, SERP-1 of myxoma virus, functions as an extracellular immunomodulator. SERP-1 is expressed as a secreted glycoprotein that protects myxoma-infected cells from clearance by macrophages and other inflammatory cells. Biochemically, SERP-1 protein binds and inhibits a spectrum of serine proteinases, such as plasmin, urokinase and tissue plasminogen activator, but its precise mode of action in virus-infected lesions remains to be elucidated. The purified SERP-1 protein alone functions as a potent antiinflammatory reagent in various animal models of inflammation.