Intensive chemotherapy with stem cell autograft is a well-established salvage treatment for relapsed/refractory lymphoma patients aged less than 65 years and it is also an effective treatment option for high-risk patients at diagnosis. Clinical applicability of autograft has been greatly amplified by the use of peripheral blood progenitor cells (PBPC), whose administration is simple and feasible, and results in lower toxicity. In addition, the development of several prophylactic measures preventing extrahemopoietic toxicities has markedly improved the feasibility and tolerability of the approach. In particular, the risk of nephrotoxicity is no more a major problem in the autograft setting since the use of proper treatments for the management of hyperuricemia, including forced hydration along with urinary alkalinization and the administration of the recombinant urate oxidase drug rasburicase. The high-dose sequential (HDS) chemotherapy program is a typical example of an intensive chemotherapy with PBPC autograft. A 15-year experience with the HDS approach in 240 lymphoma patients is reported here. The results demonstrate the clinical efficacy of HDS, with prolonged survival both in relapsed/refractory patients (54% alive) and in those treated frontline (72% alive). In addition, a very low incidence of extrahemopoietic toxicities was observed. In particular, nephrotoxicity was almost abolished, with 2 patients displaying only mild and transient renal dysfunction. In conclusion, the reported results demonstrate the therapeutic efficacy of HDS in the treatment strategy for lymphoma and emphasize the importance of delivering intensive chemotherapy with all the prophylactic measures able to minimize nephrotoxicity and other potential extrahemopoietic toxicities.