We have previously shown that intradermal coadministration of DNA encoding Bcl-x_L, an antiapoptotic protein, with DNA encoding E7 antigen linked to the sorting signal of the lysosome-associated membrane protein type 1 (Sig/E7/LAMP-1) prolongs dendritic cell life and enhances antigen presentation through the MHC class I and II pathways. In the current study, we compared this approach with a conventional DNA prime–vaccinia boost protocol on the basis of their ability to generate antigen-specific CD8⁺ memory T cells and longterm antitumor effects against an E7-expressing tumor. Mice primed and boosted with Sig/E7/LAMP-1 DNA mixed with Bcl-x_L DNA generated significantly higher numbers of E7-specific CD8⁺ memory T cells and a better long-term protective antitumor effect compared with mice primed with Sig/E7/LAMP-1 DNA and boosted with Sig/E7/LAMP-1 vaccinia (Vac-Sig/E7/LAMP-1). Furthermore, coadministration of Sig/E7 /LAMP-1 DNA mixed with Bcl-x_L DNA also generated higher avidity E7-specific CD8⁺ T cells than did vaccination with Sig/E7/LAMP-1 DNA followed by a Vac-Sig/E7/LAMP-1 booster. Our results indicate that coadministration of a DNA vaccine employing intracellular targeting strategies and a DNA encoding antiapoptotic proteins may potentially generate a higher number of memory CD8⁺ T cells and better long-term protective antitumor effects compared with the conventional DNA prime–vaccinia boost regimen.