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Background. Numerous treatment strategies have been tried with the aim of improving results for patients with intermediate-grade lymphomas (IGL) over those achieved with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo), and numerous prognostic models have been developed to identify and separate risk groups. This study reports on a new protocol for Ann Arbor Stages II-IV IGL that consists of CHOP-Bleo alternated with a new regimen of cyclophosphamide, methotrexate, etoposide, and dexamethasone (CMED) and radiation therapy and demonstrates the usefulness of prognostic models for identifying risk groups and comparing treatment programs. Methods. One hundred seventy patients with Ann Arbor Stages II-IV IGL were treated with alternating cycles of CHOP-Bleo and CMED for a total of 12 cycles. Involved field radiation therapy was interspersed with courses of chemotherapy for patients with Stage II and Stage III disease. Results were analyzed and compared with those of the authors' previous study of CHOP-Bleo and radiation therapy using the Ann Arbor staging system, their earlier prognostic model, and the recently published International Index. Results. A complete remission occurred in 78% of the patients. The overall 5-year survival rate was 67%. Survival was better for patients with Ann Arbor Stage II disease (80%) than for those with Stage III or Stage IV (67% and 58%, respectively). High tumor burden, above-normal levels of serum lactic dehydrogenase, serum β2-microglobulin, and Ann Arbor Stage IV disease were adverse factors. The International Index and the authors' earlier prognostic model separated four prognostic groups. CHOP-Bleo/CMED was generally well tolerated. Neutropenic fever was the major complication that occurred in 25 patients during treatment. Six of these patients died of sepsis. Conclusions. This study demonstrated that CHOP-Bleo/CMED is a well-tolerated regimen that produced better results than those reported for a former study that used CHOP-Bleo alone. Further, results for CHOP-Bleo/CMED compared favorably with those of other second and third-generation regimens. The study also validated the usefulness of prognostic models and, in particular, the new International Index for identifying risk groups.