Schistosomiasis remains a significant public health problem in tropical countries and it is recognized as the most important human helminth infection in terms of morbidity and mortality. Although the existing antischistosomal drugs are highly effective, they do not prevent against reinfection or granuloma formation. Therefore, vaccine strategies are essential for the control of schistosomiasis. Our group recently identified the recombinant (r) P22 protein, a component of the adult worm protein fraction PIII that has been shown to engender protective and immunomodulatory effects on murine schistosomiasis. A cDNA clone encoding rP22 was isolated from a Schistosoma mansoni adult worm cDNA library using anti-PIII rabbit serum; it exhibited complete identity with S. mansoni Sm21.7 EF-hand antigen. Confocal microscopy revealed that rP22 is a tegument protein localized on the surface of S. mansoni miracidia and adult worms. Mice immunized with rP22 exhibited a 51% and 22.5% decrease in adult worm burden and in hepatic eggs, respectively. Additionally, rP22 vaccine produced a reduction in 60% of liver granuloma size and 71% of fibrosis in mice, suggesting that rP22 might contribute to down-modulate granulomatous hypersensitivity to S. mansoni eggs. Protective immunity in mice was associated with high titers of rP22-specific IgG antibodies; elevated production of IFN-γ, TNF-α and IL-10; and a reduced level of IL-4. In conclusion, these findings indicate that rP22-based vaccines could be useful to elicit protection and reduce pathology associated to schistosomiasis.