Two different preparations of ultrapurified interferon-a (IFN-α) (lymphoblastoid and peripheral blood leukocyte) and one of IFN-γ were tested for their ability to induce terminal differentiation and alter cell growth in three human leukemia cell lines of different hematological origin (HL-60, K562, U937). Cell lines were cultured for 9 days in the presence of 500 units/ml of either IFN-α or of IFN-㚳. Cell counts and stained differentials were made on days 3, 6, and 9 to assess the effects of IFN. A marked heterogeneity of response was found, not only among cell lines, but among the IFNs tested. The most striking morphological changes were noted in the HL-60 acute promyelocytic leukemia cell line. All three IFNs tested induced significant myeloid maturation, with increased numbers of terminally differentiated myelocytes and metamyelocytes seen as early as day 3 of culture. The feasibility of using IFNs as an adjunctive or alternative therapy for the treatment of some types of leukemias is discussed. © 1984 Raven Press, New York.