Perioperative prophylaxis accounts for a substantial proportion of antibiotic use in acute-care hospitals. There is clinical evidence of its efficacy in a number of circumstances. These include hysterectomy, cesarean delivery, colorectal surgery, and some orthopedic procedures. Prophylaxis for cardiovascular surgery has not been evaluated rigorously enough to determine its efficacy. Because of the catastrophic consequences of serious infections following cardiovascular surgery, prophylaxis is widely used in this setting. There is relatively little information on the impact of prophylaxis on postoperative mortality, duration of hospitalization, or the costs of medical care. The studies that are available suggest that prophylaxis may reduce mortality and overall costs under some circumstances. Antibiotics with relatively long half-lives are theoretically attractive agents that merit careful evaluation in clinical trials. Many issues remain unresolved. The most important are the efficacy of prophylaxis in other settings, its impact on morbidity and costs, and the optimal agents and regimens.