Abstract In an effort to improve DNA vaccine immune potency electroporation has emerged as a method of delivery of plasmids to target tissues. However, few studies have examined the use of this technology to deliver plasmid vaccines to the skin. Here we studied the effect of electroporation on DNA vaccine potency and gene delivery using skin as a target tissue in larger animal species. Using a pig model, we determined that high plasmid concentrations resulted in improved gene expression for plasmid GFP delivered by the intradermal/subcutaneous (ID/SQ) route. In a macaque model, we observed higher cellular and humoral responses to an HIV DNA vaccine, which included plasmid-encoded IL-12, with electroporation compared to ID/SQ injection alone. The induced responses were T H1 mediated. These results support that skin electroporation may have importance as an immunization approach in larger animal models.