We have previously demonstrated the formation and release of influenza virus-like particles (VLPs) from the surface of Sf9 cells infected with either a quadruple baculovirus recombinant that simultaneously expresses the influenza structural proteins hemagglutinin (HA), neuraminidase (NA), matrix 1 (M1), and matrix 2 (M2), or a combination of single recombinants that include the M1 protein. In this work, we present data on the immunogenicity and protective efficacy afforded by VLPs (formed by M1 and HA) after immunization of mice. VLP vaccine ( approximately 1 microg HA) were formulated with or without IL-12 as adjuvant and administered twice, at 2-week intervals, by either intranasal instillation or intramuscular injection. All VLP-vaccinated and influenza-immunized control mice demonstrated high antibody titers to the HA protein; however, intranasal instillation of VLPs elicited antibody titers that were higher than those induced by either intramuscular inoculation of VLPs or intranasal inoculation with two sub-lethal doses of the challenge influenza virus (control group). Antibody responses were enhanced when VLP vaccine was formulated with IL12 as adjuvant. All mice were challenged with 5 LD50 of a mouse-adapted influenza A/Hong Kong/68 (H3N2) virus. Intramuscular administration of VLP vaccine formulated with or without IL-12 afforded 100% protection against a lethal influenza virus challenge. Similarly, intranasal instillation of VLP vaccine alone protected 100% of the mice, whereas VLP formulated with IL-12 protected 90% of the vaccinated mice. Not only do these results suggest a novel approach to the development of VLP vaccines for diverse influenza virus strains, but also the creation of multivalent vaccines by decoration of the surface of the VLPs with antigens from other pathogens.