Patients with polycythemia vera (PV) are most often treated with phlebotomy‐only (PHL‐O) or phlebotomy plus hydroxyurea (PHL + HU). Such treatment is often unsatisfactory because of persistent susceptibility to thrombosis owing to inadequate control of abnormal erythropoiesis and thrombopoiesis. Recombinant interferon‐α (rIFNα) inhibits erythroid progenitors and affects megakaryocyte function and thus may be a more effective treatment, but reports of its use have been of relatively short duration. The long‐term use (median, 13 years) of rIFNα in 55 patients previously treated with PHL alone or with PHL + HU was studied. Data pertaining to the natural history of the disease were also examined. Patients achieved partial response of their disease by 6 months, and complete response by 1‐2 years (phlebotomy‐free, HCT ≤45%, platelets ≤600,000/μL); spleen size was reduced in 27 of 30 patients with prior splenomegaly. The initial dose of rIFNα was 1 mega unit 3 times a week (1 MU/tiw) for the majority of patients, with periodic dose increases as required and as tolerated. The maintenance dose, usually 3 MU/tiw, could be decreased after the second year of treatment in half the patients. Toxicity was acceptable. Disease‐free survival was marked by no thrombohemorrhagic complications reflecting both the effect of rIFNα and total patient care. Evidence is presented indicating that rIFNα effectively reduces PHL requirements, thrombocythemia, splenomegaly, and thrombohemorrhagic events. It is an effective drug for treating PV with acceptable toxicity. Cancer 2006. © 2006 American Cancer Society. Long‐term interferon is effective in the treatment of polycythemia vera. It induces remission in a large percent of patients.