Chloroquine is a primary amine which inhibits in vitro cell-mediated cytolysis, probably by affecting the lysosomal system. Spontaneous and interferon (INF)-induced natural killer (NK) activities were studied in patients affected by rheumatoid arthritis (RA) undergoing chloroquine therapy. In all chloroquine-treated patients spontaneous and IFN-induced NK activities were decreased, as compared with healthy controls or RA patients, not treated with chloroquine. NK activity, however, substantially increased after withdrawal of chloroquine treatment. It is suggested that chloroquine inhibits cell-mediated cytotoxicity in vivo by the same mechanisms observed in in vitro studies, and that these effects might be relevant in the therapeutic action of this drug in RA.