Little information exists regarding the comorbidity of postoperative nonwound infections (NWIs) in patients with head and neck cancer. Prospectively, 225 patients were randomized in a double-blind fashion to receive either clindamycin or ampicillin sodium/sulbactam sodium for prevention of postoperative wound infection. Of the 113 patients receiving clindamycin, 14 developed nonwound infections, compared with 10 of 112 patients receiving ampicillin/sulbactam. A single site of nonwound infection occurred in 21 patients, and 2 sites occurred in 3 patients. The majority of infections were pulmonary (22), followed by urinary tract (3), septic phlebitis (1), and acute sinusitis (1). Gram-negative organisms were isolated more frequently among patients on clindamycin (18) versus ampicillin/sulbactam (6) (P = .014). Risk factors for pulmonary nonwound infection included: longer surgery, a greater than 70 packs per year smoking history, blood transfusion, and hypoalbuminemia (P < .05). Nonwound infections produce significant postoperative morbidity and the predominance of gram-negative organisms isolated from these infections has therapeutic implications.