Antimicrobial prophylaxis is used by clinicians for the prevention of numerous infections, including sexually transmitted diseases, human immunodeficiency virus infection, tuberculosis, rheumatic fever, recurrent cellulitis, meningococcal disease, recurrent uncomplicated urinary tract infections in women, spontaneous bacterial peritonitis in patients with cirrhosis, influenza, malaria, infective endocarditis, pertussis, plague, anthrax, early-onset group B streptococcal disease in neonates, and animal bite wounds. Certain opportunistic infections such as Pneumocystis carinii pneumonia in immunocompromised patients also can be effectively prevented with primary antimicrobial prophylaxis. Perioperative antimicrobial prophylaxis is recommended for various surgical procedures to prevent surgical site infection. Optimal antimicrobial agents for prophylaxis are bactericidal, nontoxic, inexpensive, and active against the typical pathogens that cause surgical site infection postoperatively. To maximize its effectiveness, intravenous perioperative prophylaxis should be given within 30 to 60 minutes before the time of surgical incision. Antibiotic prophylaxis should be of short duration to decrease toxicity, antimicrobial resistance, and excess cost.