Avian influenza highlights the need for novel vaccination techniques that would allow for the rapid design and production of safe and effective vaccines. An ideal platform would be capable of inducing both protective antibodies and potent cellular immune responses. These potential advantages of DNA vaccines remain unrealized due to a lack of efficacy in large animal studies and in human trials. Questions remain regarding the potential utility of cellular immune responses against influenza in primates. In this report we demonstrate that by construct optimization and in vivo electroporation of synthetic DNA-encoded antigens we observe induction of cross-reactive cellular and humoral immune responses individually capable of providing protection from influenza infection in the rhesus macaque. These studies advance both the DNA vaccines field as well as providing a novel more tolerable vaccine with broad immunogenicity to avian influenza. This approach appears important for further investigation including studies in humans.