Mouse YAC-1 and human K562 leukemic cells were treated in vitro with fibroblast interferon (IF) and tested for their susceptibility to NK effector lymphocytes. In both cases a decrease in target susceptibility was induced by the IF treatment. "Cold" competition experiments confirmed that loss or masking of NK target structures occurred in IF-pretreated cells. In fact, when radio-labeled untreated cells were used as targets, IF-pretreated leukemias produced inhibitory effects lower than those mediated by intact cells. However when IF-pretreated targets were used, cold cells either intact or preincubated with IF gave similar competitive effects. These data suggest that IF modulates differentially distinct subsets of NK target structures.