The introduction of alpha interferon in 1984 initiated a new and exciting turnaround in the treatment of hairy-cell leukemia. Until that time splenectomy was the only known effective therapy for this disease. Interferon proved to benefit hairy-cell leukemia patients with active disease, whether or not they had undergone prior splenectomy. However, most interferon-induced responses were partial and were of relatively short duration. Purine analogues such as cladribine and pentostatin have since been found to be more effective than alpha interferon and, therefore, have now replaced interferon as first-line therapy for hairy-cell leukemia. At the present time, interferon has a relatively limited role in the treatment of hairy-cell leukemia and it is reserved for a group of selected patients who have failed nucleoside analogue therapy. In this chapter, we discuss the efficacy of interferon and its response duration, toxicity and possible mechanism of action in patients with hairy-cell leukemia.