There is a requirement for a vaccine that protects against the alphavirus, Venezuelan equine encephalitis virus (VEEV). Previous work has shown that DNA vaccines encoding structural proteins of VEEV can elicit immune responses and protection against VEEV though this protection is incomplete against airborne VEEV. In this study, we demonstrate that particle-mediated epidermal delivery of a DNA vaccine encoding the E2 glycoprotein of VEEV can be boosted with a mucosally-delivered Ad-based vaccine encoding the same E2 glycoprotein. This results in an improved Th2-type IgG response, an increase in neutralising antibody and a significant increase in protection against airborne VEEV. This indicates that prime-boost may be a suitable immunisation regimen for providing protection against airborne VEEV.