Objective: To determine the relationship between frailty and comorbidity, in-hospital mortality, postoperative complications, length of hospital stay (LOS), and costs in head and neck cancer (HNCA) surgery.Study Design: Cross-sectional analysis. Methods: Discharge data from the Nationwide Inpatient Sample for 159,301 patients who underwent ablative surgery for a malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasm in 2001 to 2010 was analyzed using crosstabulations and multivariate regression modeling. Frailty was defined based on frailty-defining diagnosis clusters from the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnosis indicator.Results: Frailty was identified in 7.4% of patients and was significantly associated with advanced comorbidity (odds ratio [OR] , increased LOS (mean, 4.9 days), and increased mean incremental costs ($11,839), and was associated with higher odds of surgical complications and increased costs than advanced comorbidity. There was a significant interaction between frailty and comorbidity for acute medical complications and length of hospitalization, with a synergistic effect on the odds of medical complications and LOS in patients with comorbidity who were also frail.Conclusion: Frailty is an independent predictor of postoperative morbidity, mortality, LOS, and costs in HNCA surgery patients, and has a synergistic interaction with comorbidity that is associated with an increased likelihood of medical complications and greater LOS in patients with comorbidity who are also frail.