Four regimens of prophylactic antibiotics were utilized in 122 consecutive patients of stages III and IV carcinoma of the upper aero-digestive tract undergoing major resections in a randomized single-blind study. Ampicillin, gentamicin, cephalexin and metronidazole were used in different combinations for periods of 5 or 10 days. A cephalexin-metronidazole protocol for 10 days was associated with lowest post-operative infection rate. Oral-oropharyngeal resection and use of pectoralis major myocutaneous flap were the most important factors contributing to infection.