Th2 lymphocyte responses under the control of IL-4 and IL-5 are frequently associated with protective responses to parasitic helminths. Studies on the role of these cytokines in acquired resistance to parasitic nematodes indicate that, in the case of gastrointestinal nematodes, immunity is mediated by IL-4, while immunity to tissue-dwelling nematodes is dependent on IL-5. Here we investigate the role of IL-5 and eosinophils in protective immunity to Onchocerca microfilariae in IL-4-deficient mice. In the absence of IL-4, and despite the up-regulation of Th1-type responses, immunity remains dependent on IL-5 and eosinophils. Protection was unaffected by the absence of Ab in B cell-deficient mice, confirming that IL-5 is not acting via either B cell differentiation, Ag presentation, or isotype switching mechanisms. These data demonstrate the dissociation of IL-4 and IL-5 in a functional model of protective immunity to a tissue dwelling nematode and cast doubt on the role of IL-4 in the generation of CD4+ T cell-mediated, IL-5-dependent immunity to Onchocerca microfilariae. Importantly, they also segregate T cell-mediated mechanisms of protective immunity from those characterized in ocular pathologic responses in onchocerciasis, which are dependent on IL-4.