Objective Patients who need major head and neck surgery like laryngectomy are at risk of postoperative wound infection. Although the role of antibiotics in prophylaxis of clean contaminated head and neck surgery has been well documented, controversy exists in the optimal antibiotic regimen. Results No wound infection was detected in either 2-day group, and 3 (6.7%) in the 5-day group. There was between two groups. Methods In two tertiary referral hospitals (Imam ConclusionWe conclude that a 2-day perioperative cefazolin prophylaxis is equally effective as longer therapies. The increased morbidity and cost of the latter are in favor of the 2-day prophylactic regimen.