The properties of the recombinant DNA-derived human leukocyte interferon, HuIFNα2, were studied in patients with advanced leukemia or lymphoma. In vitro, HuIFNα2induced an increased activity of 2–5A synthe-tase in leukemic and in control cells indicating cellular responsiveness to IFN. HuIFNα2also produced a dose-responsive decline in marrow leukemia blast progenitor colony growth, and in normal hematopoietic colony formation in vitro, confirming its antiproliferative effect. A course of intravenous therapy given to a lymphoma patient produced a modest decline in peripheral white blood cell (WBC) and neutrophil counts; higher, more frequent doses in a second patient induced a profound drop in WBC's, neutrophils, and platelets. When the leukemia patients were given an intravenous course of HuIFNα2as a sole agent, blast cytoreduction was seen in peripheral blood in three patients, and in marrow of one patient with acute myeloblastic leukemia (AML). Elevated 2–5A synthetase levels could be detected after therapy. No modulation of leukemic cell markers was seen after in vitro or in vivo treatment with HuIFNα2, implying that the cytoreduction was not linked to blast cell differentiation. These studies suggest that this subtype of recombinant DNA-derived IFN has antileukemic properties, and indicates the possibilities for IFN as an adjunctive form of therapy in leukemia.