The present study has shown that in vitro antibody-dependent cellular cytotoxicity and natural cytotoxicity of human blood lymphocytes are inhibited by retinoic acid (5 X 10(-4)M). The inhibition of cytotoxicity is due to a specific effect on the effector lymphocytes and not to an effect on the target cells. The reduction of killing is most pronounced with prolonged incubation (20 h) of the killer cells with retinoic acid, recovery of killer and natural killer cell activity occurring with post-treatment incubation (greater than 24 h, 37 degrees C) in medium. Retinoic acid was found to have an antagonistic effect to interferon in modulating in vitro natural killer cell activity. The mechanism of inhibition by retinoic acid was uncertain but modulation of cell membrane receptors appeared to be a likely possibility.