Hypereosinophilic syndromes (HES) and systemic mastocytosis (SMCD) are heterogeneous disorders with clinical symptoms from local and remote effects of excessive proliferation of eosinophils and mast cells, respec tively. Interferon α (IFN-α), alone or in combination with other medications, can be a useful, and at times life-saving, treatment for patients with HES. Receptors for IFN-α are present on eosinophils, and clinical benefits are due to its effect on eosinophil proliferation, migration, activation, and survival. These effects are likely mediated through multiple pathways including, but not limited to, inhibition of eosinophil colony-forming cells, upregulation of IFN-γ synthesis, and inhibition of production of eosinophil-active cytokines by T cells, mast cells, and mononuclear cells. IFN-α has been life-saving for patients with intractable HES that were resistant to prednisone, hydroxyurea, and other agents. Resistance to the eosinopenic effect of IFN-α does not develop and the dose of IFN-α necessary to maintain control of eosinophilia often decreases with time. The combination of IFN-α and hydroxyurea is very useful and allows dosage reduction of IFN-α and better control of hypereosinophilia than with either agent alone. The efficacy of IFN-α for treatment of SMCD has been more difficult to establish, with both favorable and unfavorable results reported. The disparate results may have resulted from the small number of patients with SMCD treated with IFN-α, the use of various criteria for a ‘successful’ treatment outcome, short duration of treatment and follow-up, and the use of modest dosages. In reported series, side effects from IFN-α have frequently been dose-limiting. IFN-α improves many of the clinical symptoms of SMCD including dermatological, hematological, gastrointestinal, and systemic symptoms associated with histamine release. IFN-α has a beneficial effect on skeletal symptoms because of its ability to increase bone density and reduce painful episodes from vertebral fractures. No consistent improvement in bone marrow infiltration by mast cells has been demonstrated except in a recent study employing high dosages of IFN-α. A beneficial effect from the combination of IFN-α and prednisone has been reported for several patients, suggesting that combined use of these two medications may provide synergism in treatment outcomes.