DNA-based immunizations have been used to analyze the ability of DNA-expressed hemagglutinin (HA) and nucleoprotein (NP) to protect BALB/c mice against a homologous influenza virus, A/PR/8/34 (H1N1), challenge. The HA DNA, but not the NP DNA, protected mice against the lethal viral challenge. For the HA DNA, single gene gun inoculations of 0.04 microg and boosted inoculations of 0.004 microg of DNA raised complete protection. For the NP DNA, boosted gene gun immunizations of 0.4 microg of DNA and boosted intradermal or intramuscular injections of 50 microg of DNA failed to protect. The protection elicited by the HA DNA vaccine correlated with the titers of neutralizing antibody.