In the event of another influenza virus pandemic, strategies for effective mass vaccination will urgently be needed. We used a novel transdermal patch delivery technology, known as the PassPort system, to vaccinate mice with recombinant H5 hemagglutinin with or without immunomodulators. This needle-free form of vaccine delivery induced robust serum antibody responses that were augmented by different immunomodulators that stimulated the innate immune system and protected mice against lethal challenge with a highly pathogenic avian H5N1 influenza virus. Copyright © 2007, American Society for Microbiology. All Rights Reserved.