In an effort to protect chickens against Newcastle disease (ND), a nonreplicating virosome vaccine was produced by solubilization of Newcastle disease virus (NDV) with Triton X-100 followed by detergent removal with SM2 Bio-Beads. Biochemical analysis indicated that the NDV virosomes had similar characteristics as the parent virus and contained both the fusion and hemagglutinin-neuraminidase proteins. To target the respiratory tract, specific-pathogen-free chickens were immunized intranasally and intratracheally with the NDV virosome vaccine. This vaccine was compared with a standard NDV (LaSota) live-virus vaccine for commercial poultry. Seroconversion (≥ four fold increase in hemagglutination inhibition [HI] antibody titers) was achieved in all birds vaccinated with the virosome vaccine. Upon lethal challenge with a velogenic NDV strain (Texas GB), all birds receiving either vaccination method were protected against death. Antibody levels against NDV, as determined by enzyme-linked immunosorbent assay and HI titer, were comparable with either vaccine and increased after virus challenge. These results demonstrate the potential of virosomes as an effective tool for ND vaccination.