We aimed to validate and evaluate the comprehensive complication index (CCI) as a measure of postoperative complications (POCs) in the patients with head and neck squamous cell carcinoma (HNSCC) who had undergone free-flap reconstruction.A single-center, prospective cohort study was conducted on the patients with primary HNSCC treated between 2015 and 2020.Of 443 patients, 177 experienced POCs (40.0%). According to the new CCI, 93 patients had severe POCs (score ≥26.2; 21.0%), and only 76 patients were classified as having severe POCs (grade ≥III; 17.2%) according to the traditional Clavien-Dindo classification (CDC). The patients with CCI scores ≥26.2 had a higher rate of major adverse short-term outcomes, such as prolonged length of the hospital stay after surgery, excessive medical costs, and the need for transfusion. Importantly, the Kaplan-Meier analysis revealed a lower overall survival rate for patients with severe complications (CCI score ≥26.2, P = .038). However, no statistically significant differences were observed between CDC grades III or above and overall survival (P = .100).The CCI can be used to evaluate POCs of free-flap reconstruction in patients with HNSCC. It performed more accurately than the CDC in short- and long-term outcome prediction and risk factor identification.Copyright © 2022 Elsevier Inc. All rights reserved.