OBJECTIVE: To identify independent risk factors for enteric carriage of vancomycin-resistant Enterococcus faecium (VREF) in hospitalized patients tested for Clostridium difficile toxin. DESIGN! Retrospective case-cohort study. SETTING: Tertiary-care teaching hospital. PATIENTS: Convenience sample of 215 adult inpatients who had stool tested for C difficile between January 29 and February 25,1996. RESULTS: 41 (19%) of 215 patients had enteric carriage of VREF. Five independent risk factors for enteric VREF were identified: history of prior C difficile (odds ratio [OR], 15.21; 95% confidence interval [CI95], 3.30-70.10; P<.001), parenteral treatment with vancomycin for ≥5 days (OR, 4.06; CI95, 1.54-10.73; P=.005), treatment with antimicrobials effective against gram-negative organisms (OR, 3.44; CI95, 1.20-9.87; P=.021), admission from another institution (OR, 2.95; CI95,1.21-7.18; P=.017), and age >60 years (OR 2.57; CI95, 1.13-5.82; P=.024). These risk factors for enteric VREF were independent of the patient's current C difficile status. CONCLUSIONS: Antimicrobial exposures are the most important modifiable independent risk factors for enteric carriage of VREF in hospitalized patients tested for C difficile.