The effects of cyclosporin A (CsA) treatment and hormonal bursectomy on Eimeria tenella infection of chickens were investigated to evaluate the role of humoral antibody and cell-mediated immunity (CMI) in the host protective immunity to an intestinal protozoan disease, coccidiosis. Hormonal bursectomy had no significant effect on the host response to E. tenella. CsA treatment had a differential effect on the course of disease depending on how CsA was given relative to infection. Daily administration of CsA for 7 days beginning 1 day before primary infection with E. tenella enhanced disease resistance, whereas a single dose of CsA given before primary infection enhanced disease susceptibility compared with that of untreated controls. Chickens treated with CsA during the primary infection were resistant to reinfection at 5 weeks post-primary infection. Treatment of chickens immune to E. tenella with CsA at the time of secondary infection abrogated their resistance to reinfection despite the presence of high levels of coccidia-specific secretory immunoglobulin A and serum immunoglobulin G. Splenic lymphocytes obtained after CsA treatment demonstrated a substantially depressed concanavalin A response, but not a depressed lipopolysaccharide response. Because CsA was not directly toxic to parasites in vivo when administered during the secondary infection, these results suggest that CsA interacts with the immune system to allow priming during the primary infection, while interfering with the effector function of CMI during the secondary infection. Taken together, present findings indicate that CMI plays a major role in host protective immunity to E. tenella.