No effective vaccine exists for the human parasitic disease, schistosomiasis. We have targeted a functionally important antigen, Sm-p80 as a vaccine candidate because of its consistent immunogenicity, protective potential and important role in the immune evasion process. In this study we report that a Sm-p80-based DNA vaccine formulation confers 59% reduction in worm burden in mice. Animals immunized with Sm-p80-pcDNA3 exhibited a decrease in egg production by 84%. Sm-p80 DNA elicited strong immune responses that include IgG2A and IgG2B antibody isotypes in vaccinated animals. Splenocytes proliferated in response to Sm-p80 produced appreciably more Th1 response enhancing cytokines (IL-2, IFN-gamma) than Th2 response enhancing cytokines (IL-4, IL-10). These data reinforce the potential of Sm-p80 as an excellent vaccine candidate for schistosomiasis.