Understanding the preoperative, intraoperative, and postoperative risk factors of reoperation is the optimal way to approach decreasing its incidence. To identify risk factors of unplanned reoperation following major operations of the head and neck. This retrospective cohort study queried the American College of Surgeons National Surgical Quality Improvement Program database and identified 2475 cases of major operations of the head and neck performed between 2005 and 2014. Specific operations analyzed were glossectomy, mandibulectomy, laryngectomy, and pharyngectomy. Univariate and multivariate analyses were performed to compare demographic and clinical characteristics of patients with or without unplanned reoperation. Data were analyzed between September and November 2017. The primary outcome was incidence of unplanned reoperation in patients with major operations in the head and neck region. An additional aim was to assess the risk factors associated with an increased likelihood of reoperation. In total, 1941 patients were included in this study (1298 [66.9%] males), with most patients (961 [49.5%]) between 61 and 80 years of age. The overall unplanned reoperation rate within 30 days after the principal operative procedure was 14.2% (275 patients). The operative procedure with the highest reoperation rate was pharyngectomy (8 of 46 [17.4%]), followed by glossectomy (95 of 632 [15.0%]), laryngectomy (53 of 399 [13.3%]), and mandibulectomy (25 of 240 [10.4%]). Among the unplanned reoperation patients, 516 patients (76.8%) underwent reoperation during their initial hospital admission and 156 patients (23.2%) after readmission. The mean (SD) number of days from the principal operative procedure to unplanned reoperation was 8.5 (3.6) days for initial-admission reoperations and 16.0 (4.8) days for readmission reoperations. The most common unplanned reoperation procedures overall included repair, surgical exploration, and revision procedures on arteries and veins (47 of 2475 [1.9%]), incision procedures on the soft tissue of the neck and thorax (37 of 1941 [1.9%]), and incision and drainage procedures on the skin, subcutaneous, and accessory structures (21 of 1941 [1.1%]). Multivariate analysis results indicated that the independent risk factors for unplanned reoperation following a major cancer operation of the head or neck included black race (odds ratio [OR], 1.72; 95% CI, 1.09-2.74), disseminated cancer (OR, 1.85; 95% CI, 1.14-3.00), greater total operation time (OR, 2.05; 95% CI, 1.49-2.82), superficial (OR, 2.56; 95% CI, 1.55-4.24) or deep (OR, 4.83; 95% CI, 2.60-8.95) surgical site infection, wound dehiscence (OR, 8.36; 95% CI, 5.10-13.69), and ventilator dependence up to 48 hours after surgery (OR, 2.95; 95% CI, 1.79-4.87). The identification of a significant association of black race, disseminated cancer, total operation time, surgical site infection in either the superficial or deep spaces, wound dehiscence, or ventilator dependence for more than 48 hours after surgery with increased risk of reoperation in major head and neck surgery may guide the modification and adaptation of these risk factors to decrease the burden that unplanned reoperation places on patients, surgeons, and the health care system.