To determine the differences in outcome in cases of enterococcal bacteremia due to vancomycin-resistant organisms, we compared consecutive patients on a liver transplant service who had clinically significant bacteremia due to vancomycin-resistant Enterococcus faecium (VREF) (n = 54) with a contemporaneous cohort of patients who had vancomycin-susceptible E. faecium (VSEF) bacteremia (n = 48). VREF bacteremia occurred significantly later in the hospitalization than did VSEF bacteremia (43 days vs. 24 days, respectively; P < .01); in addition, VREF was more frequently the sole blood pathogen isolated (91% of patients) than was VSEF (56% of patients) (P = .0002). Invasive interventions for intraabdominal and intrathoracic infection were required more often in the VREF cohort than in the VSEF cohort (34 of 45 patients vs. 20 of 41 patients, respectively; P = .01). Vancomycin resistance more frequently resulted in recurrent bacteremia (22 of 54 patients infected with VREF vs. 7 of 48 patients infected with VSEF; P = .006), persistent isolation of Enterococcus species at the primary site (27 of 33 patients infected with VREF vs. 7 of 18 patients infected with VSEF; P = .005), and endovascular infection (4 patients infected with VREF vs. none infected with VSEF). The decrement in patient survival, as measured from the last bacteremic episode, was greater in the VREF cohort (P = .02). Vancomycin resistance, shock, and liver failure were independent risk factors for Enterococcus-associated mortality. Higher rates of refractory infection, serious morbidity, and attributable death occurred in the VREF cohort and were partially mediated by the lack of effective antimicrobial therapy.