Background: We did a prospective study of busulfan (bu) and fludarabine (flu) conditioning in patients with myelofibrosis. After observing a high relapse rate in the initial cohort, we increased the intensity of conditioning regimen for subsequent patients, hypothesizing that increased dose intensity delivered with PK guidance will reduce relapse rate without increasing non relapse mortality (NRM), thereby improving overall outcome. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Of the 46 consecutive patients, 15 (bu low group) received IV busulfan 130 mg/m² x 2 (day -3,-2). Of the remaining 31 (bu high group), 27 received IV busulfan dose to a target daily AUC of 4000 μmol.min x 4 (day -5 to -2) and 4 patients received a fixed dose of 100 mg/m² x 4 (days -5 to -2). All patients received fludarabine 40mg/m²x 4 (day -5 to -2). Results: 23 males and 23 females with a median age of 58 years (27-74) had intermediate (25) or high-risk (21) disease. Donors were matched sibs (19), matched unrelated (23), or mismatched unrelated (4). With a median follow-up of 2.1 years (range 0.1-6 years), 3-year overall survival(OS), event-free survival (EFS), cumulative incidence (CI) of non-relapse mortality (NRM), and CI of relapse were 69%, 50% , 13%, and 37%, respectively. Multivariate Cox regression analysis showed that Bu-high dose (HR 0.41; p=0.04) and peripheral blood CD 34 count (HR 1.7; p=0.03) were significantly associated with EFS, and high CD-34 count was significantly associated with OS (HR 1.87; p=0.04). Table shows details of 3-year outcomes of low-dose and high-dose group. All patients engrafted with a median time to neutrophil engraftment of 13 (0-27) days and a median time to platelet engraftment of 24 (0-268) days. Cumulative incidence (CI) of grade II-IV, grade III, IV acute GVHD, and Chronic GVHD were 22%, 5%, and 39%, respectively. Conclusions: Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non-relapse mortality, resulting in better EFS in patients with MF. Clinical trial information: NCT00475020.