Cell-mediated immune responses were examined in 19 normal volunteers after intranasal administration of three strains of influenza A virus. Eight volunteers manifested respiratory tract illness along with fourfold rises of serum antibody and/or virus shedding. Samples of peripheral venous blood were obtained before and two days, five days, and four weeks after challenge. During acute illness, infected volunteers showed lymphopenia, which persisted for up to four weeks after challenge. The lymphopenia involved thymus-derived, bone marrow-derived, and null cells. Blastogenic responses of lymphocytes to stimulation with phytohemagglutinin, concanavalin A, and streptokinase-streptodornase were depressed during acute illness, and responses to phytohemagglutinin and concanavalin A remained depressed at four weeks after infection. Thus, influenza infection in humans can result in prolonged depression of numbers and functions of circulating lymphocytes.