Purpose: The array of options for the initial management of follicular small cleaved lymphoma (FSCL) and follicular mixed lymphoma (FML) ranges from little or no therapy to the use of intensive combinations of drugs. The Cancer and Leukemia Group B (CALGB) compared two contrasting approaches: A single agent, and combination chemotherapy capable of curing diffuse aggressive lymphomas. Patients and Methods: A total of 228 patients with stage III or IV FSCL or FML were randomized to cyclophosphamide or the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B). Treatment was continued in responders for 2 years beyond maximal response. The primary end point was survival in the most common subtype, FSCL. Results: Ninety-one percent of all patients responded; complete responses were seen in 66% of those treated with cyclophosphamide and in 60% treated with CHOP-B (P = .36). At 10 years with either cyclophosphamide or CHOP-B, respectively, overall time to failure (25% failure free v 33%; P =.107) and survival (44% alive v 46%; P = .79) were similar by treatment. Outcomes in FSCL also were similar. In 46 patients with FML, at 10 years the combination was associated with better failure-free (9% v 48%; P = .005) and overall (25% v 61%; P = .024) survival. Acute toxic effects were more common with combination chemotherapy. Second malignancies, which might be attributed to treatment, were seen with both approaches. Conclusion: There is no advantage to the initial use of the relatively intensive combination, CHOP-B, for patients with FSCL compared with the less toxic single agent, cyclophosphamide. However, in an unplanned subgroup analysis, patients with FML who received the combination experienced improved disease control and survival.