One hundred six eligible patients with advanced intermediate- or high-grade malignant lymphoma were treated with methotrexate with leucovorin rescue, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) in a Southwest Oncology Group phase II trial. Patients were stratified by estimated bone marrow reserve, and impaired marrow reserve patients received reduced doses of cyclophosphamide and doxorubicin. The complete remission rate for normal marrow reserve patients was 65%, while the complete remission rate for impaired marrow reserve patients was 29%. With a median follow-up period of 41 months, 64% of complete responders in the normal marrow group are disease-free 3 years after their response. Three-year survival is 61% in the normal marrow reserve group and is 29% in the impaired marrow reserve group. Eighty-seven percent of treatment courses were given in accordance with protocol dosing and schedule. For doxorubicin, relative dose intensities were 0.75 and 0.61 (normal and impaired marrow reserve arms, respectively), for cyclophosphamide, 0.76 and 0.61, and for methotrexate, 0.55 and 0.45. Serum lactic dehydrogenase (LDH) level was the only pretreatment characteristic found to have a significant effect on overall survival. Severe or greater toxicity occurred in 97% and 89% of the normal and impaired marrow reserve groups, respectively, with granulocytopenia the principal toxicity. Treatment-related fatalities occurred in 8% of patients. m-BACOD is an effective but toxic treatment program for intermediate- and high-grade malignant lymphomas.