Immunization with plasmid DNA encoding various proteins promises to be a valuable vaccine approach especially if its immunogenicity could be optimized. In this study we show that the intramuscular delivery in dendritic cells (DC) of naked plasmid DNA encoding two proteins of herpes simplex virus (HSV) leads to the induction of significantly enhanced levels of resistance to viral challenge. Whereas DC transfected in vitro with DNA induced enhanced immunity, similarly transfected macrophage (Mɸ) populations lacked immunogenicity even though plasmid expression occurred in vitro. The enhanced immunity induced by DC‐delivered DNA appeared to be associated mainly with an increased Thl CD4⁺ T cell response. Our results add evidence that DC are the essential antigen‐presenting cell types involved in immune responses to intramuscularly administered DNA vaccines. J. Leukoc. Biol. 61: 125–132; 1997.