Objective: To examine use of third-generation cephalosporins (3GCs) alone and in association with vancomycin hydrochloride as a risk factor for vancomycin-resistant enterococcus (VRE) infection in surgical patients. Design: Case-control retrospective study analyzing antibiotic use in the 30 days preceding culture of VRE or vancomycin-sensitive enterococcus from an infected site. Selling: A large tertiary care teaching hospital. Patients: Surgical inpatients with VRE infections between September 3,1993, and January 29,1997, were matched with patients with vancomycin-sensitive enterococcus infections. Matches were based on surgical procedure, initial infection site, and immunosuppression. Matches were found for 32 of 50 surgical patients with VRE. Twenty matched pairs of patients were recipients of solid organ transplants. Main Outcome Measures: Multivariate logistic regression analysis was done to examine 3GCs and vancomycin as risk factors for VRE infection. Univariate analysis of use of other antibiotic agents and demographic data was also performed. Results: Multivariate analysis showed significant differences in the use of 3GCs both alone and concurrently with vancomycin. Univariate analysis also showed higher use of metronidazole, concurrent vancomycin and metronidazole, concurrent vancomycin and ceftazidime, and all antibiotics combined in patients with VRE infections. Conclusions: This matched control study showed that use of 3GCs, alone (P = .05) or concurrently with vancomycin (P = .05), was a risk factor for VRE infection in surgical patients. Judicious administration of third-generation antibiotics is warranted in surgical patients with other risk factors for VRE.