OBJECTIVE To evaluate the addition of low-dose interferon-alpha 2b to standard melphalan-prednisone therapy in patients with multiple myeloma. METHODS Randomized, multicenter, phase III study. METHODS 15 university hospitals and 92 county hospitals in Sweden, Norway, Denmark, Finland, and Iceland. METHODS 583 patients with symptomatic multiple myeloma. METHODS All patients received melphalan-prednisone every 6 weeks. Melphalan-prednisone therapy was interrupted after at least 8 courses in responding patients who achieved a plateau phase, and it was reinstituted at time of relapse. Patients randomly assigned to receive melphalan-prednisone and interferon also received interferon, 5 MU three times weekly, from the start of treatment through response, plateau phase, and relapse, until definitive failure of melphalan-prednisone occurred. METHODS Survival was the main outcome measure. Secondary measures were response rate, response and plateau phase duration, and toxicity. All analyses were done according to the principle of intention-to-treat. RESULTS 45% of patients receiving melphalan-prednisone and 44% of patients receiving melphalan-prednisone and interferon achieved at least a partial response. Response duration and plateau phase duration were longer for patients receiving melphalan-prednisone and interferon than for patients receiving melphalan-prednisone alone (P < 0.05); the difference in median duration was 5 to 6 months. Toxicity was higher with melphalan-prednisone and interferon, and this led to premature discontinuation of interferon therapy in one third of patients and to a reduced overall dose intensity for melphalan. The median survival time was 29 months for patients receiving melphalan-prednisone and 32 months for patients receiving melphalan-prednisone and interferon. The risk ratio for death for patients receiving melphalan-prednisone compared with patients receiving melphalan-prednisone and interferon was 1.02 (95% CI, 0.89 to 1.40). CONCLUSIONS Adding continuous low-dose interferon to standard melphalan-prednisone therapy does not improve response rate or survival. However, response duration and plateau phase duration are prolonged by maintenance therapy with interferon.