Background: High-dose rituximab (HD-R) combined with carmustine, cytarabine, etoposide, and melphalan (BEAM) and SCT was effective and tolerable in a single-arm study for relapsed/refractory (R/R) aggressive B-cell NHL. This is the first prospective, randomized phase 2 study comparing efficacy and safety of HD-R vs. standard-dose rituximab (SD-R) combined with BEAM in R/R-NHL. Methods: Patients with R/R-NHL (44 DLBCL, 49 others) were randomized to HD-R or SD-R using Bayesian adaptive algorithm. HD-R (1000 mg/m²) or SD-R (375 m²) were administered on days +1 and +8 after stem cell infusion. Primary endpoint: disease-free survival (DFS), defined as time from SCT to disease progression or death. Overall survival (OS) and safety analysis were secondary endpoints. Based on an intention-to-treat analysis, Kaplan-Meier estimator (DFS & OS) and Cox proportional hazards regression (multivariate analysis) were used. Results: A total of 93 patients (29% females) with a median age of 63 years (6-75) were randomized to HD-R (n = 42) or SD-R (n = 51). No significant differences in patient demographic and clinical characteristics. With a median follow-up of 4.12 years (7.92 for alive patients), the 5-year DFS and OS were 42% and 48%, respectively. We found no statistically significant differences between HD-R and SD-R in 5-year DFS (37% vs 47%; p = 0.208) and OS (42% vs 52%; P = 0.395). In multivariate analyses, only disease status before SCT [complete remission (CR) vs no CR] (HR 0.57, 95% CI: 0.35-0.95) and prior treatments received ( ≤ 2 vs > 2 lines of treatment) (HR 0.53, 95% CI: 0.32-0.89) were associated with worse DFS. Similarly, these were significant poor prognostic factors for OS. Patients who had SCT while in CR or who received ≤ 2 lines of treatment prior to SCT had better 5-year OS (57% vs 35%; P = 0.02 and 54% vs 30%, P = 0.001, respectively). No differences in G3-4 toxicities, infection rates or engraftment between both arms. Conclusions: SD-R is not significantly different from HD-R when combined with BEAM in B-Cell aggressive R/R-NHL in terms of DFS and OS. Patients in CR and those with ≤ 2 prior treatments at time of SCT have a better prognosis in both study arms Clinical trial information: NCT00472056