Previous studies have demonstrated that significant hematologic improvement occurs in the majority of patients with hairy cell leukemia (HCL) treated with partially purified or recombinant interferon (IFN). Fifty-three patients received IFN alfa-2b for at least 3 months in a dose of 2 X 10(6) U/m2 subcutaneously thrice weekly. Of the 49 patients evaluable for response (at least 6 months of IFN therapy), there were ten complete responses and 29 partial responses for a total response rate of 80%. The peripheral blood counts and bone marrow continued to improve over the course of a full year of therapy. IFN was well tolerated, with no patients discontinuing therapy because of toxicity. Transient myelosuppression occurred in most patients during the first 1 to 2 months of therapy, occasionally precipitating a transfusion requirement. After IFN treatment was discontinued, there was a marked decrease in normal marrow elements and a relative increase in marrow hairy cells. This was associated with a transient increase in normal elements in the peripheral blood. Only one of 24 patients followed after receiving IFN for a median of 8.5 months (range, 3 to 16 months) has required further therapy. We conclude that low-dose IFN alfa-2b is highly effective in advanced HCL; responding patients should be treated for at least 1 year. The decision to initiate a second course of IFN therapy should be based primarily on peripheral blood counts and the clinical status of the patient rather than on the bone marrow.