This phase II study investigated the efficacy of alternating fludarabine/mitoxantrone/ dexamethasone (FMD) with cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy for patients with high tumor burden, follicular non-Hodgkin's lymphoma. Maintenance interferon was given in a nonrandomized fashion, and a retrospective analysis of its impact was performed. A total of 87 patients were included (44 females and 43 males). The median age of patients was 56 years (range, 25-86 years). All patients had high tumor burden as defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Eighty-four percent of patients (73/87) had stage III/IV disease and 99% of patients (86/87) had good performance status. The majority of patients had not been previously treated, with only 3 patients receiving prior oral alkylators or cyclophosphamide/vincristine/prednisone (COP). A total of 637 cycles of FMD/CHOP were administered and were well tolerated during this trial, the majority on an outpatient basis. The overall response rate was 95% (79 complete response/ unconfirmed complete response/partial response) in the 83 evaluable patients. Event-free survival (EFS) was 28.7 months, with time to progression (TTP) at 29 months and time to treatment failure at 41 months. Overall survival was not reached. Patients had similar EFS and TTP as patients in the French GELF trial with a shorter duration of chemotherapy. Patients with a lower International Prognostic Index (IPI) score had better EFS when compared to those with a higher IPI score (median EFS not reached versus 22.6 months). Serum beta2-microglobulin levels were not a significant predictive factor. An informal analysis of interferon maintenance therapy suggests that patients who tolerated the immune modifier did better than those who did not. Alternating FMD/CHOP is a feasible and effective therapeutic option for patients with high tumor burden, low-grade non-Hodgkin's lymphoma. While this regimen may not offer dramatic benefit over FMD alone, it is beneficial in those patients for whom a prompt treatment response is needed.