The Hospital Infection Control Practices Advisory Committee published guidelines for prudent use of vancomycin to combat increasing resistance to antimicrobial drugs. Studies examining compliance with these guidelines primarily involve hospitalized patients. The growing practice of home use of antimicrobial drugs led to this retrospective cohort study that evaluated parenteral vancomycin use in patients receiving it through a homecare agency. We found that 39.2% of outpatients received vancomycin outside the guidelines, mainly because of prolonged empiric therapy, dosing convenience, and prolonged use after surgery. Patients were more likely to receive vancomycin appropriately if they were >65 years of age, had a history of malignancy, or were discharged from a medical service. In addition, obtaining wound cultures and attempting a microbiologic diagnosis led to more appropriate vancomycin use. Recommendations for prudent vancomycin use are often overlooked when selecting antimicrobial drugs for home infusion. The public health impact of this practice remains unknown.