Risk factors for vancomycin-resistant enterococcal (VRE) bloodstream infection (BSI) were studied at a tertiary-care hospital by comparing 46 patients with VRE-BSI with 46 randomly selected patients with vancomycin-susceptible enterococcal (VSE) BSI. Among patients with an enterococcal BSI, risk factors for mortality were determined. Independent risk factors for VRE-BSI were increasing APACHE II score (odds ratio [OR], 2.3/5-point increase; 95% confidence interval [CI], 1.4-3.9), receipt of vancomycin (OR, 11; 95% CI, 5.5-21), or diagnosis of hematologic malignancy (OR, 8.4; 95% CI, 3.9-18). After controlling for APACHE II score and gender, patients with VRE- versus VSE-BSI did not have a significantly elevated risk of mortality (OR, 3.3; 95% CI, 0.7-15). Five of 28 VRE blood isolates typed using pulsed-field gel electrophoresis had identical banding patterns. These data suggest that increasing severity of illness, underlying disease, and receipt of vancomycin are major risk factors for VRE-BSI.