Although high-dose chemotherapy followed by autologous stem cell transplantation ( ASCT) has become the standard approach for patients with relapsed/ refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL), more than 50% of patients will experience relapse following ASCT. High- dose sequential chemotherapy (HDSC) can intensify the conventional salvage treatment and improve the outcome of ASCT by maximal debulking of the tumor load with the use of non-cross resistant drugs, each at their maximal tolerated doses. We conducted a phase II study in 40 patients with relapsed/ refractory HD ( n 18) and NHL ( n 22) using HDSC followed by ASCT. Only patients sensitive to salvage chemotherapy were eligible for the protocol, consisting of three phases. Phase I consisted of cyclophosphamide (4.5 g/m(2)) followed by G-CSF and peripheral blood stem cell (PBSC) collection. Phase II consisted of etoposide (2 g/m(2)). The transplant phase consisted of mitoxantrone ( 60 mg/ m 2) and melphalan ( 180 mg/m(2)) followed by PBSC infusion. Eleven out of nineteen patients with B- cell lymphoma received rituximab. Prior to HDSC, 45% of the patients were in complete remission (CR) and 55% were in partial remission ( PR). After completion of all phases of the protocol, 35 out of 39 evaluable patients achieved CR ( 90%) and this was durable in 30 ( 75%) patients with a projected progression- free survival ( PFS) rate at 4 years of 71.7%. Treatment- related mortality rate at day _100 was 2.5% ( n = 1). At a median follow- up of 32 months ( range, 3 - 61), nine patients relapsed/ progressed and eleven patients died. The estimated 4- year PFS and overall survival (OS) were 72.2% and 47.6% in HD patients and 70.3% and 69.4% in NHL patients, respectively. Factors predicting OS were response to conventional salvage therapy and stage prior to salvage therapy. When compared to patients achieving PR, patients who attained CR prior to HDSC had a significantly higher probability of 4- year OS ( 78.4% vs 31.3%, p 0.02). Three prognostic subgroups were defined according to the score determined by stage prior to initiation of salvage chemotherapy, remission duration prior to salvage ( refractory/ early relapse vs. late relapse) and response to salvage. Prognostic score was found to predict OS, PFS and event free survival ( EFS). In conclusion, HDSC followed by ASCT is an effective salvage therapy with acceptable toxicity, allowing further consolidation of response attained by conventional salvage therapy.