Objective: To understand changes in frailty and quality of life (QOL) in frail versus non-frail patients undergoing surgery for head and neck cancer (HNC). Methods: Prospective cohort study of patients (median age 67 (50, 88)) with HNC undergoing surgery from December 2011 to April 2014. Fried's Frailty Index, Vulnerable Elders Survey (VES-13), and comprehensive QOL assessments (EORTC QLQ-C30 and HN35) were completed at baseline and 3, 6, and 12-month post-operative visits. Change in frailty and QOL over time was compared between frailty groups (non-frail (score 0), pre-frail (score 1–2), and frail (score 3–5)) using a mixed effects model. Predictors of long-term elevated frailty (12 months > baseline) were analyzed using logistic regression. Results: The study had 108 patients classified as non-frail (47%), 104 pre-frail (mean (SD) 1.3 (0.4), 45%), and 17 frail (3.4 (0.6); 7%). Frailty score decreased significantly for frail patients 3 months post-operatively (2.1 (1.0); P =.002) and remained significantly lower than baseline at 6 and 12 months (2.1 (1.4); P =.0008 and 2.2 (1.5); P =.005, respectively) while frailty score increased for non-frail patients at 3 months (1.1 (1.0); P <.001) and then decreased. Forty-eight patients (21%) had long-term elevated frailty, with baseline frailty and marital status identified as predictors on univariate analysis. The frail population had significantly worse QOL scores at baseline, which persisted 12 months post-operatively. Conclusions: Frail patients demonstrate a decrease in frailty score following surgical treatment of HNC. Frail patients have significantly worse QOL scores on longitudinal assessment and would benefit from supportive services throughout their care. Level of Evidence: 3 Laryngoscope, 131:E2232–E2242, 2021.