The possibility of increasing the responsiveness of lymphoid cells to Interferon (IFN) was investigated by studying the effect of the in vitro preincubation of spleen cells from young mice with thyroid hormone prior to the administration of IFN on their Natural Killer (NK) activity. Both physiological concentrations of T4 or T3 are able to significantly increase the boosting action of IFN on NK cells. The increase in IFN-responsiveness is observable at various IFN concentrations and the peak level of IFN-induced NK activity is reached with less than a half-optimal IFN concentration after T4 pretreatment. The effect of T4 on the IFN-sensitivity of NK cells requires a very short time, being already fully expressed after only 30 min, with minor increments at more prolonged incubation times. These results indicate for the first time the possibility of modulating the in vitro sensitivity to IFN by a hormonal approach.