Schistosoma mansoni is a blood fluke parasite responsible for schistosomiasis. The best long-term strategy to control schistosomiasis is through immunization combined with drug treatment. In this study, we cloned, expressed and purified SmTSP-2 fused to the N- and C-terminal halves of Sm29 and tested these chimeras as vaccine candidates using an adjuvant approved to be used in humans. The results demonstrated that vaccination with SmTSP-2 fused to N- or C-terminus of Sm29-induced reduction in worm burden and liver pathology when compared to control animals. Additionally, we detected high levels of mouse-specific IgG, IgG1 and IgG2a against both chimeras and significant amounts of IFN-γ and TNF-α and no IL-4. Finally, studies with sera from patients resistant to infection and living in schistosomiasis endemic areas revealed high levels of specific IgG to both chimeras when compared to healthy individuals. In conclusion, SmTSP-2/Sm29 chimeras tested here induced partial protection against infection and might be a potential vaccine candidate.