In an assessment of prospective, controlled studies of antimicrobial prophylaxis against infections following otolaryngologic surgery and neurosurgery, the English-language literature on this topic was reviewed. Rates of infection following clean otolaryngologic operations are the same for patients receiving prophylaxis and those receiving placebo. For patients with head and neck cancer, rates of postoperative infection without antibiotic prophylaxis in clean surgery are < 1% and prophylaxis is not indicated; in contrast, in clean-contaminated procedures (infection rate, 18%-87%), prophylaxis is highly protective, although several studies have shown no advantage to its prolongation beyond 24 hours. For the latter operations, drugs with adequate activity against oral anaerobes are essential, whereas the need for coverage against Enterobacteriaceae is doubtful. In clean and clean-contaminated neurosurgical procedures, the rate of protective efficacy of prophylaxis ranges between 63% and 76%. For shunt operations the available evidence favors prophylaxis, but the wide range of infections reported mandates a large-scale multicenter trial to decide the issue.