This study was undertaken to assess whether gram-negative antimicrobial coverage is required in patients undergoing head and neck oncologic surgery. Ampicillin sodium-sulbactam sodium and clindamycin phosphate were compared in a prospective, randomized, parallel, double-blind trial of 212 patients undergoing head and neck procedures involving clean-contaminated wounds. Both antibiotics were given up to 1 hour before surgery and continued at 6-hour intervals after surgery for an additional eight doses. Fourteen infections occurred in the ampicillin-sulbactam-treated group (13.3%) and 29 infections in the clindamycin-treated group (27.1%). From patients receiving clindamycin, 29 gram-negative organisms were isolated, compared with six from those patients receiving ampicillin-sulbactam. This finding supports the need for gram-negative coverage in patients undergoing clean-contaminated head and neck oncologic surgery.