The responses of congenitally athymic (Nu/Nu) rats to an initial exposure and to re-exposure to Schistosoma mansoni were compared to those manifested by thymic reconstituted (Nu/Nu*TxR), heterozygous littermate controls (Nu/+) and the highly characterized Fischer rat strain. Congenitally athymic rats rejected the developing worms of an initial infection more slowly than did thymic reconstituted or heterozygous animals. These latter responses were highly comparable to those demonstrated by the Fischer rat. In addition, the congenitally athymic rats manifested lower peripheral blood eosinophilia in response to infection. Resistance to reinfection in athymic animals was impaired and associated with a decreased immunoinflammatory histologic response to hepatic intravascular parasites and to eggs lodged in the hepatic vasculature. There was little evidence of inflammatory responses involving degranulating eosinophils, lymphocytes, or macrophages in the athymic rats. Finally, athymic animals produced antibody that was less capable of passively transferring resistance in adoptive-challenge experiments; however, antibody produced in heterozygous animals conferred significant resistance when adoptively transferred to athymic animals. These results suggest that resistance to initial and subsequent challenge by S. mansoni infections in the rat is highly reliant upon T-dependent mechanisms that result in the production of antibody-dependent, possibly cell-mediated resistance. Additional studies utilizing in vitro analysis of a variety of antibody functions to define the mechanisms of T-dependent immunologic resistance in the congenitally athymic rat are the subject of the accompanying manuscript.