Fourteen patients with poor-prognosis intermediate- to high-grade non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection (12 patients) or human T-cell leukemia virus type I (HTLV-I) infection (two patients) received cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and etoposide 240 mg/m2 administered as a continuous intravenous (IV) infusion over 4 days (infusional CDE); treatment was repeated every 28 or more days for up to six cycles. All HIV-positive patients had at least one poor prognostic feature, which included either extranodal disease (10 patients), Karnofsky performance status less than 70% (six patients), a CD4 count less than 100/microL (six patients), or a prior history of acquired immunodeficiency syndrome (AIDS; one patient). Both HTLV-I-positive patients had an elevated serum lactate dehydrogenase (LDH) level, a poor prognostic feature in that setting. Complete response (CR) occurred in 10 patients (71%; 95% confidence interval, 48% to 95%) and partial response (PR) occurred in three patients (21%), yielding an overall objective response rate of approximately 93%. The estimated Kaplan-Meier median survival was 17.4 months; seven of 12 HIV-positive patients are alive and disease-free with a median follow-up of 15 months (range, 7 to 24 months). Hospitalization was required after 19% of treatment cycles due to fever associated with granulocytopenia. Documented or suspected opportunistic infection occurred in five patients (36%), bacteremia occurred in three patients (21%), and candidemia occurred in one patient (7%). There was one treatment-related death attributable to disseminated aspergillosis. This pilot study suggests that infusional CDE may be a highly active regimen capable of producing durable remissions in a high proportion of patients with HIV-related NHL. Further study is required to confirm this observation.