Morphological examination of both the lung and liver stages of Schistosoma mansoni infection in the CDF rat was conducted to further define the interactions of host cells with developing schistosomula. Examination of the developing schistosomula in the lungs revealed that all worms observed were in the vasculature, usually wedged in a vessel just large enough to accommodate the worms and a few erythrocytes. No concentrations of granulocytes or mononuclear cells were seen in direct contact with worms. Examination of livers 17–19 days postinfection showed a similar intravascular location for the worms. There was a striking perivascular response in the livers of infected rats, consisting of numerous eosinophils, frequent mast cells and macrophages, as well as mononuclear cells. No cells from this response were observed in direct contact with the schistosomula. In challenge exposures, the portal venules containing schistosomula were surrounded by an intense perivascular accumulation of eosinophils, macrophages, mast cells, and plasma cells. Fibroblasts and intercellular deposition of collagen in the inflammatory focus were also evident. Granulocytes, primarily eosinophils, were observed in the blood spaces near the schistosomula. This secondary cellular response differed from the initial hepatic lesion in containing increased numbers of mast cells and plasma cells, and in the presence of perivascular fibrosis.