The lymph nodes which drain the sites of percutaneous vaccination with optimally irradiated cercariae of Schistosoma mansoni were surgically excised in studies to determine their role in the induction of protective immunity. Lymphadenectomy of the axillary and inguinal nodes which drain the abdominal exposure site, or of the cervical node which drains the aural site of exposure, five days prior to vaccination reduced the levels of resistance by two-thirds. Excision of these nodes on Days 5, 10, 15, or 20 postvaccination also significantly reduced the levels of immunity induced, though ablation was less effective at later times. Removal of lymph nodes not draining the site of vaccination had no effect on the induction of resistance. We interpret the results as indicating that successful vaccination of mice against S. mansoni requires the presentation of antigen to lymphocytes in local lymph nodes draining the vaccination site, rather than distant lymphoid organs such as the spleen.