Cytokine and proliferative responses to Necator americanus infection were measured in a treatment-reinfection study of infected subjects from an area of Papua New Guinea where N. americanus is highly endemic. Before treatment, most subjects produced detectable interleukin (IL)4 (97%), IL-5 (86%), and interferon (IFN)-γ(64%) in response to adult N. americanus antigen. Pretreatment IFN-γ responses were negatively associated with hookworm burden, decreasing by 18 pg/mL for each increase of 1000 eggs/gram (epg) (n = 75; P < .01). Mean IFN-γ responses increased significantly after anthelmintic treatment, from 166 to 322 pg/mL (n = 42; P < .01). The intensity of reinfection was significantly negatively correlated with pretreatment IL-5 responses, decreasing by 551 epg for each 100 pg/mL increase in production of IL-5 (n = 51; P < .01). These data indicate that there is a mixed cytokine response in necatoriasis, with worm burdenassociated suppression of IFN-γ responses to adult N. americanus antigen. Resistance to reinfection is associated with the parasite-specific IL-5 response