The National Foundation for Infectious Diseases and Centers for Disease Control and Prevention recently published specific strategies that hospitals can implement to prevent and control the emergence and spread of antimicrobial resistance. One of these strategies is to optimize the choice and duration of empirical antibiotic therapy. The goal of this study was to prospectively evaluate empirical antimicrobial prescribing at a large university teaching hospital using the suggested outcome and process measurements. A total of 137 patients who received empirical therapy during May 1996 were reviewed. Nearly half were prescribed empirical therapy for surgical prophylaxis; the potential cost savings was $92 per treatment course. Other areas of empirical therapy that resulted in increased expenditures, adverse effects, and superinfections included continuation of empirical therapy despite negative culture results in 45 patients (37%) and failure to modify therapy based on culture and sensitivity results in 12 patients (9%). Inappropriate empirical therapy can lead to significant cost and negative outcomes.