Schistosomiasis mansoni is a widespread parasitic infection that may lead to several serious complications, such as hepatic periportal fibrosis and portal hypertension, mainly due to deposition of schistosome eggs in the tissues. However, people in endemic areas infrequently exhibit severe pathology and complications; this may be explained, in part, by modulation of the disease in indigenous populations by in utero exposure to the parasite. This study investigated the differences between mice born to Schistosoma mansoni-infected mothers and those born to non-infected ones in subsequent postnatal schistosomal infections. We found that the intensity of infection, evidenced by hepatic egg load, was much reduced in mice born to infected mothers. No difference was found as regards total and Schistosoma-specific immunoglobulin levels except for total IgG. The levels of gene expression of two regulatory cytokines, namely interleukin-12 (IL-12) and transforming growth factor beta (TGF-beta) were found to be significantly increased in prenatally exposed animals. Moreover, liver fibrosis was significantly decreased in animals born to infected mothers as revealed by histopathological and histochemical examination as well as by immunohistochemical identification of activated hepatic stellate cells (HSCs) using antibody against glial fibrillary acidic protein (GFAP). In conclusion, congenital exposure to S. mansoni seems to ameliorate the immunopathological changes in future postnatal infections.