Mice were vaccinated with a DNA plasmid encoding the haemagglutinin (HA) antigen of H5N1 influenza A/Vietnam/1194/2004 by particle mediated epidermal delivery (PMED). Vaccination led to potent anti-HA serological responses that were significantly enhanced by the inclusion of a plasmid expressing the A and B subunits of Escherichia coli heat labile enterotoxin (designated DEI-LT). Mice were vaccinated with H5 or H5/DEI-LT and challenged with 100LD50 H5N1 A/Vietnam/1194/2004 virus. Vaccination provided considerable protection, and mice that received two doses (prime-boost) of H5/DEI-LT showed no symptoms of disease post vaccination, did not shed detectable virus and did not show any rise in anti-H5N1 HI titre post challenge, indicating that they were fully protected. These results demonstrate that the PMED technology may hold promise for the prophylaxis of pandemic influenza.