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Background: We analyzed the effect of peri-transplant prophylaxis on the epidemiology of bacteremia in a 12-year contemporary cohort of allogeneic HSCT recipients at our center., Methods: This was an observational study of 1052 consecutive adult HSCT from 2000 to 2011. Formal prophylaxis with vancomycin only, fluoroquinolone (FQ) only, or vancomycin + FQ was implemented in 2006. The cumulative incidence of day 100 bacteremia was compared between the Early Period (2000-2005) and the Recent Period (2006-2011). Predictors for pre-engraftment bacteremia were analyzed with Cox-proportional hazard models in a subcohort of 821 HSCT who received myeloablative or reduced intensity conditioning (MA/RIC)., Results: The incidence of bacteremia decreased in the Recent Period (32% vs 27%; P = 0.002), whereas the rates of resistance in gram-negative rods (GNR) and vancomycin-resistant enterococci (VRE) were similar between the two Periods (P values are not statistically significant.) In multivariate analyses, prophylaxis with vancomycin only or vancomycin + FQ was protective (HR = 0.5; CI = 0.30-0.72) and (HR = 0.3; CI = 0.12-0.52, P < 0.01). Vancomycin or vancomycin + FQ eliminated viridans streptococcal bacteremia (VSB); vancomycin + FQ decreased GNR bacteremia (HR = 0.35; CI = 0.15-0.85)., Conclusions: Vancomycin-based prophylaxis peri-transplant in MA/RIC HSCT was associated with elimination of VSB and may be considered at centers with high incidence of this infection., (Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)