Background The efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse aggressive non-Hodgkin’s lymphoma classified as high-intermediate risk or high risk around the International Prognostic Index remains controversial and is untested in the rituximab era. or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival. Results Of 370 induction-eligible patients 253 were randomly assigned to the transplantation group (125) or the control group (128). Forty-six patients in the MRS 2578 transplantation group and 68 in the control group had disease progression or died with 2-year progression-free survival rates of 69 and 55% respectively (hazard ratio in the control group vs. the transplantation group 1.72 95 confidence interval MRS 2578 [CI] 1.18 to 2.51; P = 0.005). Thirty-seven patients in the transplantation group and 47 in the control group died with 2-year overall survival rates of 74 and 71% respectively (hazard ratio 1.26 95 CI 0.82 to 1 1.94; P = 0.30). Exploratory analyses showed a differential treatment effect according to risk level for both progression-free survival (P = 0.04 for conversation) and overall survival (P = 0.01 for conversation). Among high-risk patients the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group. Conclusions Early autologous stem-cell transplantation improved progression-free survival among patients with high-intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved probably because of the effectiveness of salvage transplantation. Autologous stem-cell transplantation has long been known to improve both progression-free survival and overall survival among patients with diffuse aggressive non-Hodgkin’s lymphoma in second remission.1 When it became possible to identify patients at diagnosis who have less than a 50% chance of sustained remission as defined by the International Prognostic Index2 (IPI) (see Table S1 in the Supplementary Appendix available with the full text of this article at NEJM.org) trials of up-front transplantation in this group were conducted. In the first trial LNH-87 patients received fullcourse induction chemotherapy regardless of their IPI risk category; those with a complete response were randomly assigned to transplantation or consolidation chemotherapy.3 Although a survival advantage was not seen with MRS 2578 transplantation a retrospective subgroup analysis showed improved progression-free survival and overall survival among patients with high-intermediate-risk or high-risk disease.3 Results of phase 2 trials suggested a benefit of consolidative transplantation in high-risk groups4 5 however few of the subsequent phase 3 trials showed a benefit.6-14 Numerous factors complicated interpretation of the results of these trials including insufficient sample size as a result of high dropout rates which were due to early disease progression or a patient’s decision to decline treatment as well as trial designs that differed from that of LNH-87. Thus 15 years after the first description of a potential benefit of consolidative transplantation in high-risk disease no role for this treatment has been clearly established. Given the limitations in comparing data from previous trials because of differences in study design we evaluated the MRS 2578 efficacy of autologous stem-cell transplantation using a design similar to that of LNH-87. Patients with high-intermediate-risk or high-risk disease who had a response to five cycles of cyclophosphamide doxorubicin vincristine and prednisone (CHOP) induction chemotherapy were randomly assigned either to one additional cycle of PIK3CD induction chemotherapy plus transplantation or to three additional cycles of induction chemotherapy. Patients with early disease progression and patients who elected not to undergo transplantation did not proceed to the randomization stage of the study which minimized dropout. Patients in the control group who had a relapse were encouraged to undergo salvage transplantation so that the efficacy of early versus delayed transplantation strategies could be evaluated. After about one third of the patients had.