INTRODUCTION: The production of a vaccine against schistosomiasis would be a valuable addition to the measures currently in use to control and, ultimately, eradicate this disease. We advocate to the use of multiple immunogenic epitopes, located at the host-parasite interface and associated with protective responses against schistosomes. Endemic area studies showed changes in antibody levels and classes after treatment with Praziquantel (PZQ), which have been associated with resistance to reinfection or low egg burden. Our working hypothesis is that it would be possible to explore the response in these individuals in order to identify epitopes associated with resistance for the rational design of a schistosome vaccine. METHODS: Subjects from an endemic area for schistosomiasis (Conde-BA) were followed up for 18 months after PZQ treatment with serum and stool sampling at 0, 1, 6, 12 and 18 months. Individuals who remained egg-negative (Kato-Katz) along the study were deemed resistance to reinfection (RR) and those who became re-infected were categorized as susceptibility to reinfection (SR). Antibody responses to tegument membranes (SmTeg) or soluble worm antigens (SWAP) were assessed by ELISA (IgG1, IgG4 and IgE). Next, the sera (IgG) from both groups (RR=9 and SR=8) were used to screen peptide microarray to identify epitopes in 55 secreted or exposed proteins from alimentary tract or tegument. RESULTS: ELISA data revealed that the RR individuals presented higher levels of IgG1 and IgE antibodies against SmTeg and SWAP, respectively. Regardless the serum analyzed (RR or SR), the most reactive proteins were the tegument target Sm25, followed by the esophageal gland proteins MEG-12 and MEG-4.1, the gastrodermal carrier LAMP, and then tegument enzyme ADP-ribosyl cyclase. The overall profile of RR and SR responses, revealed greater reactivity of SR sera against esophageal gland and gastrodermis proteins, whereas the RR group showed greater reactivity against tegument targets. Remarkably, two tegument targets (Sm25 and ADP-ribosyl cyclase) revealed three conspicuous epitopes differentially recognized by the serum of RR individuals. CONCLUSION: In spite of the high variation in epitope recognition, the strategy was useful for mapping epitopes differentially recognized by individuals selected by their history of resistance or susceptibility to S. mansoni reinfection after PZQ therapy. Perhaps not coincidentally, the Sm25 and ADP-ribosyl cyclase epitopes mapped here were the most reactive epitopes among the tegument targets previously identified by the attenuated cercariae vaccine. The results presented here combined with the mapping from other protective models provided a list of peptides that are under investigation in multiepitope vaccine constructs.