OBJECTIVE We evaluated the vincristine, doxorubicin, and dexamethasone (VAD) regimen alone or with chemosensitizers for remission induction and interferon (IFN) versus IFN plus prednisone (IFN/P) for remission maintenance in previously untreated multiple myeloma. METHODS Two hundred thirty-three patients were registered for remission-induction therapy with VAD or VAD plus the chemosensitizers verapamil and quinine. Patients who achieved remission were randomized to maintenance therapy with IFNalpha 3 MU in the evening three times weekly or IFN plus 50 mg of prednisone (IFN/P) on the morning after IFN until relapse. RESULTS Two hundred twenty-nine patients were eligible for induction. Fatal toxicities in nine patients who received VAD plus verapamil and quinine led to closure of this arm after 47 registrations. Subsequently, all patients received VAD induction. Despite the high early mortality rate on VAD plus sensitizers, overall survival by induction arm did not differ for median or 5-year survival with approximately 40% of patients surviving 5 years. Eighty-nine eligible patients who achieved remission were randomized to maintenance. Patients who received IFN/P had improved progression-free survival (median, 19 v9 months for IFN; P = .008). After 48 months, progression-free survival on IFN/P was at the thirtieth percentile, whereas it was below the tenth percentile on IFN alone. Median survival from start of maintenance was long on both arms (57 months for IFN/P v 46 months for IFN; P = .36). CONCLUSIONS IFN/Pwas more effective than IFN alone. Improved relapse-free survival may be attributable to IFN/P or to the use of prednisone for maintenance. This latter alternative is currently being studied.