The Southwest Oncology Group (SWOG) began testing doxorubicin-containing combination chemotherapy in 1972 using the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen. Subsequent studies, including 350 patients followed for up to 13.3 years, demonstrated that CHOP was curative in 32% of advanced stage, diffuse large cell lymphomas. More recently, promising results from several institutions suggest that new combinations including methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone (m-BACOD), prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate (ProMACE-CytaBOM), and methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin (MACOP-B) may be superior to CHOP as gauged by complete response (CR) rates. Consequently, the SWOG developed a strategy to compare these regimens directly with CHOP. In 1984 the SWOG began testing these regimens in sequential group-wide phase II trials to confirm therapeutic activity, establish feasibility with regard to toxicity in a cooperative group setting, and gain experience using the complex schedules and dose-modification schemes. Those phase II studies have been completed, and preliminary results indicate that these regimens are active (CR rates, 53% to 65%) and feasible to administer in a cooperative group setting (fatal toxicity, 2% to 6%). We conclude that these three drug regimens can be administered safely in a cooperative group setting, and the CR rates support the current SWOG comparative trial using CHOP as the standard treatment arm.