In order to evaluate the role of Mitoxantrone in the therapy of non-Hodgkin's lymphoma (NHL) (intermediate-high grade malignancy) a series of successive phase II-III studies were performed in a multicenter cooperative group. The first phase II study consisted of Mitoxantrone alone administered at 14 mg/m2i.v. on day 1 and repeated every 3 weeks for six times. Fifteen refractory or relapsed patients (pts) entered the study, and an overall response of 54% (CR 4 pts, PR 4 pts) was obtained. 7 pts progressed or remained stable disease (NR).The second phase II consisted of Mitoxantrone in combination with Etoposide and Prednisone (VeMP). Twenty pts were treated and a complete remission (CR) of 50% with 1 partial remission (PR) were obtained with an overall response of 55%. The third phase II study consisted of 13 pts with refractory or relapsed disease treated with Mitoxantrone, Cis-platinum, Etoposide and Prednisone (CEMP); an overall response of 62% was obtained with an acceptable toxicity. This was not superior to other conventional salvage regimens.On this background a phase III study with VEMP (Etoposide, Cyclophosphamide, Mitoxantrone, Prednisone) was started as first line therapy for pts presenting one or more of following criteria: Performance Status (P.S.) 2–3, aggressive histology at stage I-IIE or advanced stage in old pts, low grade histology with B-symptoms stage in III-IV, age over 65 years.Until now 64 pts entered this study. At present 61 pts areévaluable for response: CR was obtained in 43 pts (70%), PR in 9 pts (15%), progression disease (PD) in 9 pts (15%) 4 pts relapsed within one year after the CR.These data suggest that the VEMP combination (VEMP) is safe and as effective as other more aggressive regimens. Moreover the low hematological and general toxicity indicate this regimen as useful especially for pts not eligible for anthracycline-including protocols, and old aging pts.