Thirty-three previously untreated patients with multiple myeloma were randomized to either a combination of recombinant interferon-alpha-2C (rIFN-alpha-2C) plus vincristine/melphalan/cyclophosphamide and prednisone (VMCP) or VMCP chemotherapy alone. The combined regimen effected 67% responses and 26% minor responses, while 35 and 47% of VMCP-treated patients had a pathologically documented remission, respectively. Despite the somewhat earlier achievement and duration (12.0 vs. 8.0 months) of objective response, and the marginal survival benefit observed in the rIFN-alpha-2C + VMCP treatment arm, a significant improvement in therapeutic gain by adding a biologic response modifier to conventional first-line polychemotherapeutic drug treatment in myeloma patients has not yet been achieved. The combined regimen was well tolerated without unusual or unexpected toxic effects.