Emergency physicians are often confronted with situations in which a patient with an acute injury is at high risk for an infection. Although most traumatic wounds have a low risk for developing infection, certain types of high-risk trauma justify antimicrobial prophylaxis. This article reviews antimicrobial wound infection prophylaxis for high-risk traumatic wounds, including the prevention of rabies and tetanus. Prophylaxis to prevent infections related to invasive procedures in the emergency department is also addressed.