Anaerobic organisms are thought to be an important source of wound infection in head and neck oncologic surgery. Antibiotic prophylaxis consisting of agents specific for anaerobes combined with broad-spectrum agents that provide coverage for other well-recognized pathogens should be an effective combination regimen for this group of patients. We conducted a prospective, randomized study comparing the efficacy of prophylaxis using combination of metronidazole and cefazolin-designated group A, to prophylaxis using cefazolin alone-group B, for patients undergoing oncologic procedures of the head and neck. The rate of wound infection in the cefazolin-metronidazole group (158 patients) was 9.5%, compared with 18.6% in the cefazolin group (172 patients) (p = 0.03). Patients undergoing clean procedures had a 4.9% infection rate overall, compared with 17.9% for clean-contaminated procedures, and 33.3% for contaminated procedures. The average length of hospitalization was 20.7 days for patients who developed infections, compared with 8.9 days for patients without infection. Anaerobic organisms were cultured in 12 of 26 patients, ten of whom did not receive metronidazole. The lower rate of wound infection among patients who received metronidazole suggests that anaerobic organisms are an important source of wound infection in head and neck oncologic surgery. Chemoprophylaxis for these patients should, therefore, include specific anaerobic coverage in addition to the broad-spectrum agents that cover the more familiar aerobic organisms.