C57Bl/6 mice develop significant levels of protection to a challenge infection after percutaneous exposure to irradiated Schistosoma mansoni cercariae. Although some circumstantial evidence has suggested that antigen-presenting cells (APCs) within the skin play a role in priming anti-schistosomula effector mechanisms, no direct evidence has been presented. In this study, we describe efforts to directly test whether skin-resident APCs exposed to irradiated cercariae are capable of mediating responses consistent with previously proposed mechanisms associated with delayed-type hypersensitivity reactions. We demonstrate that a population of APCs emigrates from the skin after percutaneous vaccination and that these cells are able to induce proliferation of S. mansoni–specific lymphocytes. We describe our experiments conducted to confirm that proliferation is dependent on major histocompatibility complex (MHC) Class-II interactions and cell-to-cell contact between APCs and lymphocytes. Immunohistological staining of emigrating cells revealed a population of large MHC Class-II cells with a morphology characteristic of mature dendritic cells. On recovery and adoptive transfer into naive mice, these cells demonstrated the ability to mediate protection to a challenge infection at levels similar to those in percutaneously vaccinated controls. This confirms that cutaneous APCs can initiate anti–schistosomula effector mechanisms in C57Bl/6 mice after percutaneous vaccination.