Perioperative antibiotic prophylaxis has been demonstrated to prevent postoperative wound infection after clean surgery in a majority of clinical trials with sufficient power to identify a 50% reduction in risk. The low risk of infection after many clean procedures requires studies of more than 1,000 procedures (sometimes many more) to detect such reductions reliably. This is a serious obstacle to performing conclusive tests of efficacy, and it all but precludes use of conventional clinical trials to identify optimal regimens. Regimens that have been shown to be effective have usually been those with efficacy against Staphylococcus aureus and other pathogens that may be carried in the nares or on the skin. In addition, relatively long half-life in the serum and low cost are important considerations. Cefazolin is a good prophylaxis agent for many clean surgical procedures, although special characteristics of the procedure, increased likelihood of antimicrobial resistance, or antibiotic utilization concerns may make other agents more suitable in specific situations The decision to use perioperative antibiotic prophylaxis for clean surgical procedures depends not only on its efficacy, but also on the cost of preventing infection. Few cost-benefit analyses have been performed, especially for procedures in which prophylaxis has been least used. To perform such analyses, it will be necessary to acquire information that is currently lacking for many procedures. This includes the risk and cost of postoperative infection, adverse reactions to the prophylaxis agent, and increased antimicrobial resistance; in addition, detailed information is needed on infection-associated costs of medical care, lost productivity, and the value that the infected person places on avoiding infection. For many procedures, timely use of an appropriate antibiotic is the single most effective infection prevention method that can be implemented and monitored on a broad scale. These features make it amenable to adoption as a subject of continuous quality improvement activities. To accomplish this, it is necessary to articulate standards of care clearly so that systems to support the intended goal can be developed. Both the standards and the support systems can be tailored to specific surgical situations and to the values of providers and patients.