Schistosomiasis is a chronic parasitic disease affecting mostly low income and resourcelimited countries. Despite the distribution of the curative medicine, praziquantel (PZQ), the frequency of re-infection is commonly reported, thus, making a difficulty to discriminate treatment failure after re-infection. Therefore, assessing Schistosoma mansoni re-infection after praziquantel administration is crucial to prove the treatment efficacy and to break the transmission of infection in endemic areas. The evolution of highly sensitive and specific diagnostic markers, reliable to detect the re-infection and to evaluate the treatment efficacy, is required to control schistosomiasis. In this study, the potential role of serpin recombinant antigen of S. mansoni as a biomarker of re-infection and chemotherapeutic efficacy has been assessed. Therefore, 20 mice were experimentally challenged and re-challenged with 50 S. mansoni cercariae and divided into 4 equal groups; the first included infected mice (control positive), the second group was twice infected with S. mansoni and left untreated, the third included mice twice infected then treated with praziquantel following the last challenge, and the forth one remained uninfected and untreated (control negative). The current findings demonstrated that high levels of IgG and IgG1 bound to serpin were detected following the re-infection and rapidly declined post treatment. In summary, S. mansoni recombinant serpin could be used as a promising marker to discriminate S. mansoni re-infection and evaluated the efficacy of treatment. The translation of such a potential tool in endemic areas will provide a significant support for the elimination and control programs against schistosomiasis.