Nucleic acid-based vaccines are effective in infectious disease models but have yielded disappointing results in tumor models when tumor-associated selfantigens are used. Incorporation of helper epitopes from foreign antigens into tumor vaccines might enhance the immunogenicity of DNAvaccines without increasing toxicity. However, generation of fusion constructs encoding both tumor and helper antigens may be difficult, and resulting proteins have unpredictable physical and immunologic properties. Furthermore, simultaneous production of equal amounts of highly immunogenic helper and weakly immunogenic tumor antigens in situ could favor development of responses against the helper antigen rather than the antigen of interest. We assessed the ability of 2 helper antigens (β-galactosidase or fragment C of tetanus toxin) encoded by one plasmid to augment responses to a self-antigen (lymphomaassociated T-cell receptor) encoded by a separate plasmid after codelivery into skin by gene gun. This approach allowed adjustment of the relative ratios of helper and tumor antigen plasmids to optimize helper effects. Incorporation of threshold (minimally immunogenic) amounts of helper antigen plasmid into a DNA vaccine regimen dramatically increased T cell-dependent protective immunity initiated by plasmid-encoded tumorassociated T-cell receptor antigen. This simple strategy can easily be incorporated into future vaccine trials in experimental animals and possibly in humans.