This study evaluated the prophylactic use of cefazolin in reducing the incidence of infection in patients undergoing cancer surgery where the upper aerodigestive tract was entered from the neck. A prospective, randomized, double-blind design was conducted in a single hospital. The patient was given placebo or cefazolin, 1 gm intramuscularly with the preoperative medications, then 0.5 gm every six hours for four doses. Of 55 determinate patients, 32 received antibiotics and 23 placebo. Infection rate was 38% (12/32) and 87% (20/23) respectively, representing a statistically significant reduction in infection (P < 0.001). There were 30 wound and two nonwound (sinusitis and pneumonia) infections. In conclusion, the perioperative use of cefazolin in patients undergoing cancer surgery where the oral cavity or pharynx has been entered from the neck is useful in reducing the incidence of wound infection.