One hundred thirty-eight patients with hairy cell leukemia were randomized to receive either a dose of 2.0 megaunits (MU)/m2 or a 10- fold lower dose of 0.2 MU/m2 of a highly purified natural alpha- interferon, administered daily for 28 days followed by a three times a week schedule. Ninety-seven of these patients had previously undergone splenectomy, but otherwise none of the patients had received prior therapy for their leukemia. The two doses were comparable in their effect on improving the neutrophil and platelet count, whereas the higher dose had a greater beneficial effect on the hemoglobin level and a greater antileukemic effect on the marrow. Acute toxicity in the form of a flu-like syndrome, neurologic side effects, neutropenia, and the need for platelet transfusions was observed less frequently in the low- dose group, as was the chronic fatigue syndrome. No neutralizing antibody activity was seen in the sera from 61 patients examined. Because of its beneficial effect on the neutrophil and platelet count and a lower degree of toxicity (ie, a superior therapeutic/toxicity ratio), the low dose is recommended as initial therapy in patients with hairy cell leukemia. This therapy may be followed by dose escalation once clinical improvement is observed.