This prospective, randomized trial was designed to determine the efficacy and mechanism of action of topical mouthwash versus parenterally administered perioperative prophylactic antibiotics in contaminated head and neck surgery. Patients were randomly assigned to 1 of 4 treatment groups: 1 day of parenteral clindamycin (standard prophylaxis), 1 day of topical clindamycin, 5 days of topical clindamycin, or 1 day of topical amoxicillin plus clavulanate/ticarcillin plus clavulanate. Patients who received the latter regimen had fewer bacteria postoperatively compared with the other 3 treatment groups. The number of gram-negative aerobic bacilli on postoperative oral cavity cultures was increased in all 3 clindamycin groups but not in the amoxicillin plus clavulanate/ticarcillin plus clavulanate group. Parenteral clindamycin appears to exert its effect by being in the neck tissues at the time of surgery; however, all 3 topical regimens were more effective at reducing the number of bacteria in the neck viscera. Topical antibiotic prophylaxis was simple, safe, effective, and well tolerated.