The incidence of NHL associated with HTV infection continues to rise despite advances in anti-retroviral therapy (ART), and the optimum chemotherapy regimen for this disease remains to be defined. We performed a dose-escalation trial to determine the maximum tolerated doses (MTD) of etoposide (E) and doxorubicin (A) as part of a 12 week chemotherapy regimen VACOP-B supported by G-CSF in patients (pts) with AIDS-related NHL. Pts were age 18, previously untreated, and had aggressive histology/high-grade NHL with no active opportunistic infection. Pts received cyclophosphamide 350 mg/m2 weeks 1,5,9; vincristine 2 mg and bleomycin weeks 2,4,6,8,10,12; prednisone 100 mg q2days x 12 weeks; ara-C 50 mg IT weeks 1,4,8,12; E and A were escalated as follows: Dose Level (mg/m2) Route Weeks 12 3 45 Etoposide IV dl 25 25 37.5 37.5 50 pod 2,3 3,7,11 50 50 75 75 100 Doxorubicin IV dl 1,3.5.7,9,11 25 37.5 37.5 50 50 Number of pts 78 8 5 19 G-CSF was given days 4-6 in weeks 3,7,11, and days 2-6 all other weeks to prevent febrile or treatment-day neutropenia. The 5th dose level was expanded to permit full-dose ART in the last 10 pts. All pts received prophylactic fluconazole and cotrimoxazole daily. A total of 47 patients were enrolled on this trial: median age 37 (range 27-67); PS: 0-8%, 1-44%, 2-42%, 3-4%. Histology: DLBC: 49%, Burkitts 13%, IBL 23%, other 8%; 2 extranodal sites: 17/47 (36%). Results: Protocol-defined MTD was not reached and limits of DLT not exceeded, even in the group of pts receiving ART. A total of 468 weeks of therapy were delivered; only 32 treatments (4.9%) were delayed 6 days due to toxicity, 13 (2.8%) for neutropenia. 30/47 pts (64%) completed all 12 weeks of therapy. There was 1 treatment-related death. Response to therapy: CR 13 (28%) PR 5 (10%), PD 28 (59%). Median time to progression is 9 months; at 42 months, PFS and OS are 18% and 27%, respectively. VACOP-B chemotherapy can be given in standard doses to pts with HIV and NHL when supported by G-CSF and is well tolerated, even combined with ART, but long-term NHL control is poor and new therapies are needed in this disease.