Influenza virus (H3N2) host cell variants isolated from a single infected individual were compared for their protective efficacies when used as formalin-inactivated purified whole virus vaccines in ferrets. A/Mem/12/85 virus grown in embryonated chicken eggs (egg-grown), which differs from A/Mem/12/85 grown in mammalian Madin-Darby canine kidney cells (MDCK-grown) by a single amino acid substitution in the hemagglutinin molecule, was shown to be distinguishable by immune ferret serum. Ferrets were immunized intramuscularly with intact inactivated MDCK- or egg-grown virus and were subsequently challenged with infectious virus grown in either host cell type. MDCK-grown-virus vaccine induced higher mean serum hemagglutination-inhibiting (HAI) and neutralizing antibody titers than did egg-grown-virus vaccine and induced superior protection of ferrets against subsequent challenge with infectious virus grown in either host cell type. These results suggest that human influenza viruses that are antigenically and structurally similar to viruses grown in mammalian cells may be more efficacious as vaccines than some variants selected in eggs.