The interleukin-17 (IL-17) family, especially IL-17A, plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). This study developed an IL-17A epitope vaccine to treat SLE in NZBWF1 and MRL/lpr mouse models. A plasmid vector encoding a hepatitis B core (HBc)-IL-17A epitope fusion protein was injected using electroporation into the skeletal muscle of NZBWF1(New Zealand Black mice x New Zealand White mice F1 hybrid strain) or MRL/lpr mice three times at 2-week intervals. As a result, anti-IL-17A antibodies were successfully produced in the HBc-IL-17A group. Accordingly, serum tumor necrosis factor alpha (TNF-α) concentrations were significantly reduced in the HBc-IL-17A group. According to pathological analysis, the IL-17A DNA vaccine significantly suppressed renal tissue damage and macrophage infiltration. Consequently, the survival rate was significantly improved in the HBc-IL-17A group. In addition, we evaluated the antigen reactivity of splenocytes from IL-17A-immunized mice using an enzyme-linked immune absorbent spot (ELISPot) assay for safety evaluation. Splenocytes from IL-17A-immunized mice were significantly stimulated by the HBc epitope peptide, but not by the IL-17A epitope or recombinant IL-17A. These results indicate that the IL-17A vaccine did not induce autoreactive T cells against endogenous IL-17A. This study demonstrates for the first time that an IL-17A DNA vaccine significantly reduced organ damage and extended survival time in lupus-prone mice.