The purpose of this analysis was to determine the most important factors contributing to operative wound infections for patients with head and neck cancer. Four hundred cases were studied prospectively at M. D. Anderson Cancer Center within an 18-month interval. Potential risk factors were categorized based on the patient, the disease, and the treatment. Sixty-three (19.75%) wound infections were recorded. Univariate analysis identified the following factors to significantly alter the incidence of the infection: nutritional status and alcohol consumption (patient factors); T stage and N stage (disease factors); and duration of surgery, type of surgical wound, complexity of the procedure, use of flaps, blood replacement and the use of drains, nasogastric tubes, and tracheostomies (treatment factors). A logistic regression analysis identified the type of surgery, the choice of antibiotic, the presence of concomitant disease, and the N stage to represent the combination of factors most predictive of infection. The initial step toward preventing surgical wound infection is to identify the high-risk factors. The results of this study help to define these parameters so that specific measures can be taken to counteract wound infection.