Interferons (IFN) have clinical efficacy in certain hematologic malignancies. Combining IFN with conventional cytotoxic agents has been proposed as a means of improving therapy for diseases such as chronic myelogenous leukemia (CML). In this study, we examined the effect of recombinant interferons alone and in combination with Ara-C on normal and leukemic human hematopoietic progenitor cells (CFU-GM) in vitro. Mononuclear cells from normal bone marrow, peripheral blood of patients with CML, or the acute nonlymphocytic leukemia cell line HL-60 were incubated with alpha-, beta-, or gamma-IFN (0-1,000 units/ml) followed by the addition of Ara-C. The survival of normal CFU-GM was significantly increased if cells were treated with IFN 1 h before 3 h of Ara-C exposure. Similar IFN pretreatment of CML and HL-60 progenitors failed to protect leukemic CFU-GM from Ara-C-induced toxicity. This selective protection of normal CFU-GM may have clinical application.