OBJECTIVE The role of interferon (IFN) in the remission phase of multiple myeloma (MM) is still an open question, particularly for its scheduling and the subset of patients who could benefit from this approach. The present randomized multicenter study was designed to compare two schedules of IFN maintenance therapy in order to assess the difference in effectiveness and tolerance. METHODS This prospective randomized multicenter study was attempted to assess the best schedule of IFN administration in the maintenance treatment of MM in plateau phase with regard to progression free survival (PFS) and toxicity. The second aim was defining the difference between the two schedules in overall survival (OS) and identifying the critical dose of IFN therapy needed to prolong plateau phase and survival. We enrolled 52 patients affected with low-risk MM (i.e. with serum beta 2-microglobulin < 6.0 mg/L and serum albumin > 3.0 g/dL); 27 patients (group A) were randomly assigned to receive IFN alpha-2b 3 megaunits (MU) subcutaneously three times a week and 25 patients (group B) 3 MU/day until disease progression. RESULTS Median progression free survival (PFS) was 11.9 months in group A and 38.3 months in group B (p = 0.0038). Median survival was 63.2 months in group A and 61.9 months in group B (p = 0.489). However, those patients who were given an IFN dose > or = 30 MU/month experienced a significantly longer PFS and survival than the other patients. Seventeen patients (32.7%) discontinued therapy and sixteen patients (30.8%) reduced IFN alpha-2b dose because of severe side effects without having a significant difference between the two schedules. CONCLUSIONS Our results show that patients treated with IFN alpha 3 MU/day had a significantly longer remission duration than patients treated with IFN alpha 3 MU three times weekly. Moreover, an IFN dose is probably critical for obtaining a longer survival in patients affected with low-risk MM. Since the patients' discomfort during a IFN maintenance therapy was frequently experienced the quality of their lives should be carefully taken into account.