The mechanism of lysis of influenza virus-infected BHK-21 cells by guinea pig serum (GPS) was investigated. Lysis was shown to involve activation of the classical complement pathway and was dependent on the presence of a mannose-binding lectin in GPS. FACS analysis demonstrated Ca(2+)-dependent binding of the lectin to influenza virus-infected, but not uninfected, cells. Cells infected with mutant strains of virus lacking a particular high-mannose oligosaccharide at the tip of the hemagglutinin molecule showed reduced binding of the lectin and were correspondingly less sensitive to lysis by GPS than cells infected with the parent viruses. The degree or pattern of glycosylation of influenza viruses thus influences susceptibility to this mechanism of viral clearance. By interfering with the infectious process, lectin-dependent complement-mediated lysis of infected cells may be an important component of innate immunity to influenza and other enveloped viruses.