The effect of skin application of N,N-diethyl-m-toluamide (DEET) on the penetration and migration behavior of cercariae of Schistosoma mansoni was evaluated in vitro and in vivo in a mouse model. These studies showed that DEET at concentrations of 7.5% or higher was 100% effective in immobilizing and killing cercariae of S. mansoni in vitro. Ultrastructural studies on such DEET-exposed cercariae showed transformative and degenerative changes involving both tegument and deeper parenchymal structures. Fatal tissue lesions were evident as early as 5 min postexposure to DEET, and became more extensive with increasing exposure time. Cutaneous application of DEET (as a pure chemical in isopropanol or as a commercial insect repellent preparation) was more than 99% effective in preventing entry of S. mansoni cercariae into the mouse tail skin. Radiolabeling and tracer studies confirmed that 7.5% DEET applied to the skin prior to infection was highly effective in preventing schistosomular migration to the lungs.