The prevention of wound infection after major contaminated head and neck surgery is a critical issue for the head and neck surgeon. The proper interpretation of cultures taken from wounds is uncertain. Multiple organisms are invariably isolated from this nonsterile site including indigenous aerobic and anaerobic flora, aerobic gram-negative rods, and fungi. We present evidence from controlled antibiotic trials that demonstrate the pathogenicity of oropharyngeal anaerobic flora. The presence of aerobic gram-negative rods and fungi generally represent colonization and antibiotic coverage need not routinely be directed at these organisms. On the other hand, the antibacterial spectrum of an agent used for head and neck would prophylaxis should include coverage for pathogenic oral flora, namely the gram-positive aerobic cocci (especially streptococci) and anaerobic bacteria.