Concentrations of 0.1 to 10.0 micrograms of cyclosporin A (Cy A) per ml do not directly inhibit the lysis of 51Cr-labeled K562 target cells by human peripheral blood natural killer (NK) cells nor of antibody-coated chicken red blood cells by antibody-dependent cellular cytotoxicity (ADCC) effector cells. Pretreatment of effector cells with Cy A for 18 hr still failed to affect NK or ADCC effector function. However, induction of NK cell activity by overnight pretreatment of effector cells by polyinosinate-polycytidylate (PolyIC) is inhibited by as little as 1 micrograms of Cy A per ml. The mechanism of inhibition may involve a direct effect of Cy A on "induced" or "activated" NK cells or inhibition of the release of Poly IC-induced interferon from lymphocytes.