This study aimed at restricting expression of DNA vaccine to specific cell types by using skin-specific promoters (i) to contribute to the understanding of the mechanism of intradermal DNA vaccines and (ii) to address safety concerns associated with DNA vaccines. The expression and immune response after delivery of plasmids encoding luciferase by intradermal DNA electroporation were assessed. Two ubiquitous promoters, CMV and CAG, and three tissue-specific promoters were studied. Keratin 14 promoter restricts gene expression to keratinocytes of the epidermal basal layer, CD11c promoter to dendritic cells and fascin promoter only to mature dendritic cells. The use of plasmids with tissue-specific promoter resulted in significant, but very low protein expression, as compared to that obtained with ubiquitous promoter plasmids. Immunisation with both ubiquitous promoter plasmids elicited humoral and cellular anti-luciferase immune response. No immune response was observed after delivery of CD11c plasmid while fascin and keratin 14 plasmids induced IFN-gamma response suggesting that the targeting of skin-specific cells could be a suitable approach but only for the treatment of pathologies or pathogens requiring mainly cellular and not humoral immune response.