Methionine aminopeptidase 2 (MAP2) is an essential enzyme that is involved in protein maturation. It plays a key role in the removal of the initiating methionine residue from nascent polypeptide chains. In the present study, a gene encoding methionine aminopeptidase 2 of Schistosoma japonicum (SjMAP2) was cloned and characterized. Real-time RT-PCR and Western blot analysis revealed that this was expressed in each testing developmental stage in S. japonicum, but more highly expressed at 42 days in male adult worm, suggesting this gene as male differentially expressed. The results also showed that the gene was differentially expressed in worms from three different host species. It was highly expressed in worms from the schistosome-susceptible mouse, expressed at a lower level in worms from the less susceptible rat, and at an even lower level in worms from the non-permissive host Microtus fortis. The expression of the gene was affected significantly when the hosts were treated with praziquantel: Expression was down-regulated by 92.17% and 49.01%, respectively, in treated male and female adult worms in comparison with untreated worms. An immuno-experiment in mice indicated that vaccination with recombinant SjMAP2 could induce partial protective efficacy against schistosome infection. The data presented here suggest that SjMAP2 is an important molecule in the development of the schistosome and that it may be a potential new drug target or vaccine candidate for schistosomiasis.