T-cell recognition of cancer neoantigens is important for effective immune-checkpoint blockade therapy, and an increasing interest exists in developing personalized tumor neoantigen vaccines. Previous studies utilizing RNA and long-peptide neoantigen vaccines in preclinical and early-phase clinical studies have shown immune responses predominantly driven by MHC class II CD4 T cells. Here, we report on a preclinical study utilizing a DNA vaccine platform to target tumor neoantigens. We showed that optimized strings of tumor neoantigens, when delivered by potent electroporation-mediated DNA delivery, were immunogenic and generated predominantly MHC class I-restricted, CD8 T-cell responses. High MHC class I affinity was associated specifically with immunogenic CD8 T-cell epitopes. These DNA neoantigen vaccines induced a therapeutic antitumor response , and neoantigen-specific T cells expanded from immunized mice directly killed tumor cells These data illustrate a unique advantage of this DNA platform to drive CD8 T-cell immunity for neoantigen immunotherapy.