Background: High-dose therapy and autologous stem cell transplantation (ASCT) in patients (pts) with aggressive B-NHL failing from immunochemotherapy including rituximab show poor outcome with 3y PFS of 39% (Gisselbrecht et al. JCO 2010). Combining BEAM with ⁹⁰yttrium ibritumomab tiuxetan is a promising option to enhance the efficacy of the high-dose regimen. Methods: Pts without disease progression during salvage therapy of relapsed or refractory CD20+ aggressive B-NHL were included in this prospective, multicenter, phase I/II trial. Primary endpoint was the maximum tolerated dose of ⁹⁰Yttrium ibritumomab tiuxetan given as close as possible to ASCT defined as <2 pts with dose limiting toxicity in a 6+6 pts cohort. First, we reduced the time interval of ⁹⁰yttrium ibritumomab tiuxetan (0.4 mCi/kg body weight) to ASCT from 14 to 12 and then 10 days. Subsequently it was planned to increase the ⁹⁰yttrium ibritumomab tiuxetan dose. Results: From 2006 to 2009 26 pts, median age 58y (34-66) were enrolled. Histology included 14 DLBCL, 6 FL III°, 5 transformed FL and 1 aggressive B-NHL without further subtyping. 11/26 pts had relapse/progression within 1y after diagnosis. Secondary IPI was >1 in 14 pts. Response to salvage therapy was CR in 6/26 pts and PR in 12/26 pts. 20/26 pts achieved CR after ASCT. Engraftment showed no significant differences in pts of different cohorts with median recovery of leukocytes (>1/nl) and platelets (>25/nl) at d +10 and +13. Two early deaths (d +7, +18) occurred due to infections. ⁹⁰Yttrium ibritumomab tiuxetan (0.4 mCi/kg body weight) at d -10 of ASCT was determined as minimum tolerated interval of radioimmunotherapy to ASCT after BEAM. Median follow-up of the survivors is 3.3 y. 3y PFS and OS is 67% (95% CI, 49%-85%) and 75% (95% CI, 58%-92%), respectively. Main cause of death was relapse/progression with 27% (95% CI, 6%-38%) at 3y. Conclusions: Z-BEAM followed by ASCT was safe and feasible and results in a high response rate with durable remissions in rituximab pretreated patients with aggressive B-NHL. Extended studies at the maximum tolerated dose and confirmation of superiority compared to conventional ASCT are warranted.