The present pilot study was designed to analyze the efficacy and toxicity of the association of natural α-interferon (nIFN), melphalan, and prednisolone in untreated patients with multiple myeloma. Nine patients were treated with conventional melphalan-prednisolone therapy. Another 15 patients were treated with the combination therapy of nIFN, melphalan and prednisolone. We concluded that treatment with nIFN is beneficial because of the good response rate and improvement in the synthesis of serum immunoglobulins. However, adverse reactions to nIFN were sever when the patients were treated with daily intramuscular injection of 6 × 106U/body of nIFN. Thus, we have started a randomized study which includes daily intramuscular injection of 3 × 106U/body of nIFN.