Forty-nine patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma underwent autologous hematopoietic stem cell transplantation (autoHSCT) using the regimen of busulfan (Bu), cyclophosphamide (Cy), and etoposide (E) that was originally developed for allogeneic HSCT. Eighteen patients treated before 1999 received Cy 2.5 g/m2 on days -3 to -2 and E 1800 mg/m2 on day -3 after oral (PO) administration of Bu 1 mg/kg every 6 hours × 4 days for a total of 16 doses beginning on day -7. After April 1999, 31 patients similar in all pretransplantation risk assessments received the same regimen except that intravenous (IV) Bu was substituted for PO Bu and pharmacokinetic-directed (PKD) dosing was attempted to achieve an area under the concentration time curve of 1000-1500 μmol/min for each dose. Nonrelapse mortality was 28% for PO Bu patients versus 3% for the IV PKD group (P = .01, chi-square test). Actuarial 5-year overall survivals were 28% for patients who received the PO Bu regimen and 58% for patients who received the IV Bu regimen (P = .010, log-rank test), and progression-free survivals were 17% and 50%, respectively (P = .008, log-rank test). After substitution of PKD IV Bu in the BuCyE regimen, we observed lower nonrelapse mortality with increased overall and progression-free survivals in patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma who underwent autoHSCT. © 2006 American Society for Blood and Marrow Transplantation.