objective. To identify independent risk factors associated with isolation of linezolid-resistant, vancomycin-resistant Enterococcus (VRE).design. A retrospective, case-case-control study.setting. A tertiary care, academic medical center.methods. VRE isolates from clinical cultures were retrospectively analyzed for linezolid resistance during our 18-month study period. Clinical data were obtained from electronic patient records, and the risk factors associated with isolation of linezolid-resistant VRE were determined by comparison of 2 case groups with a control group.results. A total of 20% of the VRE isolates analyzed during the study period were linezolid resistant, and resistant isolates were most commonly recovered from the urine (40% of resistant isolates). Risk factors found to be associated with isolation of linezolid-resistant VRE were peripheral vascular disease and/or the receipt of a solid organ transplant, total parenteral nutrition, piperacillin-tazobactam, and/ or cefepime. Only 25% of patients from whom linezolid-resistant VRE was isolated had previous linezolid exposure, and in the multivariate model this was not found to be a risk factor associated with the isolation of linezolid-resistant VRE.conclusions. The results of this analysis suggest that there is horizontal transmission of linezolid-resistant VRE in our institution and highlight the need for improved infection control measures. Furthermore, the high incidence of linezolid-resistant VRE demands a reassessment of our empirical antibiotic selection for patients infected with VRE.