Purpose: In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkin's disease. We compared these regimens as initial chemotherapy for Hodgkin's disease. Patients and Methods: Adult patients (N = 856) with advanced Hodgkin's disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies. Results: The rates of complete remission (76% v 80%, P = .16), failure-free survival at 5 years (63% v 66%, P = .42), and overall survival at 5 years (82% v 81%, P = .82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P = .060 and .001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P = .057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P = .13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P = .011). Conclusion: ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkin's disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkin's disease.