Purpose To evaluate the feasibility and activity of a second line chemotherapy regimen consisting of VP16, mitoxantrone and prednimustine (VMP) in patients with relapsed or resistant HIV related non-Hodgkin's lymphoma (HIV-NHL). Patients and methods Twenty-one patients were consecutively treated Thirteen patients were resistant to primary chemotherapy and eight patients had relapsed after first complete remission (CR). VP16 and prednimustine were both given orally at doses of 80 mg/m 2 daily for 5 days, and mitoxantrone was given i.v. at a dose of 10 mg/m 2 on day 1; cycles were repeated every three weeks. Results Nineteen out of 21 patients are evaluable for response. The median number of cycles actually administered was 2 (range 1–5). A CR occurred in 5 out of 19 patients (26%; exact 95% confidence interval: 9% to 51%). Four of these CRs were observed in the 7 evaluable relapsed patients. Out of 45 cycles evaluable for toxicity, severe neutropenia (<5OO/mI) occurred in 19 (42%) cycles and severe thrombocytopenia (<25.000/ml) in 6 (13%) cycles. One toxic death occurred due to a sepsis during neutropenia. The overall median survival was 2 months (range, <1–13); the median survival time for the 5 patients with CR (13 months, range 6–13) was statisticallty significant longer (p = 0.004) than that observed in patients without CR (2 months, range <1.7). Conclusion Although the overall prognosis of patients with resistant and relapsed HIV-NHL is very poor, palliative therapy with VMP can be effective and relatively safe. Prolonged survivals have been observed in some patients who had relapsed after initial chemotherapy. Supported by AIRC 95 grants.