Errors in antimicrobial prophylaxis for surgical patients remain one of the most frequent types of medication errors in hospitals. Failure to administer the first dose of antimicrobial prophylaxis within the 2-h window of time before incision is associated with 2- to 6-fold increases in rates of surgical site infection. Optimal use of antimicrobial prophylaxis includes proper case selection; use of appropriate agents; proper dosing, route of administration, timing, and duration; and intraoperative dosing when appropriate. Effective use of antimicrobial prophylaxis also requires monitoring of and feedback on patterns of use. Programs to improve antimicrobial prophylaxis should be multidisciplinary and should aim to improve use of medications, not simply to change physician practice patterns. The LDS Hospital experience demonstrates the clinical and financial benefits of such a program and also shows the pitfalls of and great difficulties associated with changing systems of care.