Current control programs against schistosomiasis could be reinforced through the use of an effective vaccine. Schistosome 14-3-3 proteins have been proposed as candidates for vaccine against the respective infections, and were seen to elicit high protection levels against Schistosoma bovis in a previous work done by our group. We have therefore investigated the protective capacity of the 14-3-3 protein from S. bovis - Sb14zeta - against Schistosoma mansoni in mice. In addition, we have addressed the influence of the co-administration of three different immunomodulators with the 14-3-3 polypeptide. Protection was high when the Sb14zeta protein was combined in two independent experiments with the AA2829 and PAL immunomodulatory molecules as regards both the reduction of worm numbers (mean: 64.8%) and egg loads in liver (mean: 73.9%) or intestine (mean: 71.5%). In contrast, the degree of protection achieved with the Sb14zeta-CpG vaccine was very low (14.9% reduction in worm numbers, and 46.6% and 32% reduction in liver and intestinal egg loads). The immune responses observed in the vaccinated animals showed that the production of IFNgamma and the absence of IL-4, accompanied by a strong humoral response, are insufficient to elicit protection against S. mansoni.