Mice vaccinated with an aqueous extract of Onchocerca lienalis microfilariae (mf) plus adjuvant exhibited 51% protection against challenge with live mf. Protection was ablated by prior treatment of the extract with heat or proteinase K, indicating the involvement of proteinaceous epitope(s). A 54% level of protection was conferred on naive mice by passive transfer of serum from vaccinated donors, suggesting that host resistance was principally mediated by humoral components of the immune response. In contrast, the protection induced by sensitization of mice with living mf is transferable with cells, but not serum. Western blot data reveal different antigen recognition profiles for serum antibodies from these two groups of mice. These results indicate that vaccination and infection activate distinct protective mechanisms against Onchocerca mf in the mouse.