The temporal effects were studied of a single dose of hydrocortisone acetate on the development and expression of immune responses to Plasmodium berghei in mice with chronic infections. Cortisone administration prior to primary infection reduced malaria-specific secondary humoral and cellular responses, as well as the ability to survive parasite challenge. Once protective humoral immunity was established after chemotherapy of primary infection, cortisone treatment did not disrupt its expression. Administration of cortisone during subpatent chronic infection resulted in a transient recrudescence of parasitemia not apparent in untreated mice. Clearance of recrudescence or parasite challenge was associated with a rapid cortisone-resistant antibody response. During subpatent chronic infection, malaria-specific antibody levels were reduced, whereas delayed-type hypersensitivity (DTH) to malaria antigens and heterologous antigens was well developed. At least two systems of immunity to malaria appear to be present during chronic infection. Recrudescence of parasitemia may be prevented by antibody-independent, cortisone-sensitive cellular immunity. Once parasitemia becomes overt after cortisone treatment, or parasites are reintroduced with challenge, cortisone-resistant humoral immunity appears to mediate parasite clearance. Regulation of these systems may be a dose-dependent phenomenon which results in the persistence of parasites, albeit at subpatent levels.