BACKGROUND. alpha-IFN is reported to be an effective treatment for a number of lymphoproliferative diseases. Little information is available at present on its effect in unaggressive immunoproliferative disorders. STUDY DESIGN AND RESULTS. In a prospective non randomized study, 57 patients with IgG or IgA MGUS, smouldering myeloma or stage I MM treated with alpha-IFN (3 MU 3 times a week for at least 6 months) were compared to 129 untreated similar patients. Four patients in the IFN group showed a monoclonal component reduction > 50% versus none in the control group, and 25% of patients suffered disease progression (MC increase > 50% and/or osteolytic lesions) in the IFN group as compared to 18% in the control group. CONCLUSIONS. alpha-IFN administration at the dose used is ineffective for the majority of patients with slowly proliferating immunoproliferative disorders; only a small subgroup of them may benefit from such a treatment.