Ferrets were immunized with two 7- mu g doses of hemagglutinin from inactivated whole-virus vaccines containing the hemagglutinin gene of A/Duck/Singapore/3/97(H5N3) then inoculated with a lethal dose of A/Vietnam/1203/04(H5N1) (Viet/1203/04). Serum samples did not react with Viet/1203/04 in hemagglutination-inhibition (HI) or virus-neutralization (VN) tests. All vaccinated ferrets survived the challenge, whereas all mock-immunized ferrets died. Immunized ferrets had significantly lower virus titers in the upper respiratory tract and less-severe disease. Vaccine generated from antigenically different H5 virus protects against infection by a highly pathogenic H5 strain. Neither HI nor VN testing provides correlates of cross-protection in ferrets.