Interferon (IFN) caused the transfer of natural cytotoxic activity between human leukocytes in a syngeneic system. The transfer of cytotoxic activity was found to be dependent on the cell density and was in proportion to the IFN concentration. Human immune-type IFN (IFN-gamma) was more efficient than IFN-alpha or IFN-beta in eliciting the transfer of cytotoxic activity. The transfer occurred with IFN-gamma preparations of various specific activities and with recombinant IFN-gamma. The transferred activity had the characteristics of an IFN-induced antiviral state, in that it was blocked either by actinomycin D or by prevention of cell contact. Specific antibodies to IFN had no effect on the transfer of cytotoxic activity. Protection of mouse target cells from human cytotoxic activity could also be transferred from IFN-induced human foreskin fibroblasts (HFF) insensitive to cytotoxic activity to the cytotoxic-sensitive mouse cells. The transfer of protection was highly efficient at ratios of one HFF cell to 16 mouse target cells. The transfer of cytotoxic activity, and protection from cytotoxic activity, may represent a mechanism for amplification of the IFN system as a host defense against viral-infected or tumor cells.