The protective efficacy of a Schistosoma japonicum, Chinese strain, triose-phosphate isomerase (TPI) plasmid DNA vaccine was examined in naïve pigs. Pigs were vaccinated with the TPI DNA-plasmid alone, or in conjunction with IL-12 as pcDNA3.1-P35, pcDNA3.1-P40 plasmids via intramuscular injection. Control pigs were immunized with equivalent amounts of pcDNA3.1. Pigs were immunized 3 times at 21-day intervals and challenged 30 days after the final boost. Forty-five days post-challenge, pigs were sacrificed and perfused to compare adult worm burdens, female worm burdens, liver egg burdens and granuloma size. We found that pigs vaccinated with SjCTPI DNA alone had adult worm burdens reduced by 48·3% and that a further decrease in adult worm burdens was not seen in the group vaccinated with SjCTPI DNA in conjunction with IL-12 (46·2% reduction). The SjCTPI DNA vaccines had a more pronounced effect on reducing female worm burdens i.e. 53·6% SjCTPI alone and 59·6% for SjCTPI+IL-12. Vaccination with SjCTPI-DNA reduced liver eggs by 49·4% and this response was significantly enhanced by the addition of IL-12 (65·8% reduction in liver eggs). In addition to the dramatic protective effects seen in vaccinated pigs, we also noted that granuloma size was reduced by 42% in both groups. Thus, vaccination of pigs and other large animals in China with SjCTPI DNA vaccine will likely reduce transmission by reducing adult worm burdens and worm egg output and simultaneously reduce hepatic egg-associated pathology.