From July 1971 to August 1975, 63 previously untreated patients with stage IV non-Hodgkin's lymphomas with favorable histologies were prospectively randomized to three treatment programs: cyclophosphamide, vincristine, and prednisone alone (CVP); split course CVP and total lymphoid irradiation (CVP-TLI); or single alkylating agent (SA) therapy. More than 95% of all patients responded to therapy, and pathologically documented complete remissions were achieved in 78.3% of CV, 65% OF CVP-TLI, and 55% of SA patients (p greater greater than 0.2). The actuarial probability of obtaining a complete remission was the same (greater than 80%) for SA patients as it was for those receiving CV or CVP-TLI, but the time required to achieve a complete remission was more prolonged for SA patients (up to 40 mo). Only six (14.3%) complete responders have relapsed; the others have remained relapse-free for periods of 1–35 mo. There have been no statistically significant differences noted among the groups in terms of the probability of disease-free survival or survival, and 82.7% of all patients are alive at 30 mo (84.6% CVP, 73% CVP-TLI, and 90% sa). all three treatment programs have thus been highly effective in achieving excellent responses and prolonged disease-free survivals in patients with stage IV non-Hodgkins lymphomas with favorable histologies. Over the 4-yr period of study, single agent therapy has been associated with as good or better overall survival when compared to the more aggressive treatment programs (CVP and CVP-TLI).