A significant proportion of Schistosoma mansoni schistosomula die soon after penetration of mammalian host skin. This study was conducted to further define the host cellular response which occurs in the skin and which may contribute to early schistosomulum death in the resistant CDF rat and the more susceptible BALB/c mouse. In primary abdominal skin exposures of both hosts the initial 6-hour response is marked edema and epidermal cell disruption in the schistosomulum penetration tracts accompanied by migration of neutrophils to surround the parasites and into damaged areas of the epidermis and dermis. Challenge exposures in previously infected hosts result in more intense exudative inflammation than is observed in initial exposures with the additional infiltration of eosinophils into the dermis and epidermis. Mast cells are numerous and are occasionally observed degranulating. By 24 hours following either initial or challenge exposures the infiltration of granulocytes is more intense. Focal areas of neutrophils, eosinophils, and necrotic cells are frequent in the epidermis. Postcapillary venules contain large numbers of granulocytes. The vascular endothelium is frequently vacuolated and occasionally exhibits focal degeneration. Rat hosts show responses which are qualitatively similar to those in mouse hosts but quantitatively more intense. Smaller numbers of eosinophils were observed in the immune mouse at 24 hours than have been reported in previous studies. This may be attributable to differences in strain, in the time course of response in abdominal as compared with ear skin, or in the levels of immunity in the animals used.