BACKGROUND: Polyetheretherketone and titanium mesh are commonly used in skull repair, but there is no clinical trial evidence of long-term (such as 2 years after operation) repair effect and safety comparison between the two materials. OBJECTIVE: To evaluate the long-term effect and adverse events of polyetheretherketone and titanium mesh in repairing skull defects. METHODS: This is a prospective, single-center, non-randomized controlled, 2-year follow-up clinical trial. Sixty inpatients scheduled for skull repair in the Fourth Affiliated Hospital of China Medical University will be enrolled and divided into two groups according to different intraoperative skull repair materials. Polyetheretherketone and titanium mesh materials will be used in the trial and control groups, respectively (n=30 per group). All patients will be followed up for 6, 12, and 24 months. This trial was approved by the Medical Ethics Committee of the Fourth Affiliated Hospital of China Medical University on February 1, 2021 (approval No. EC-2021-HS-002). This trial meets the requirements of the Declaration of Helsinki formulated by the World Medical Association. All patients are required to sign an informed consent form. The recruitment time will be from August 1, 2021 to August 1, 2022. Result analysis time will be from September 1, 2024 to September 30, 2024. Completion time will be October 31, 2024. RESULTS AND CONCLUSION: Primary outcome measure is rate of failure in skull repair at 24 months after surgery. Secondary outcome measures are rate of failure in skull repair at 6 and 12 months after surgery; the incidence of adverse events to assess safety of implant materials; Glasgow Outcome Scale scores to evaluate the recovery of neurological function; satisfaction score for body shaping to assess skull shaping effect; and head CT imaging to assess skull injury healing at 6, 12, and 24 months after surgery. Cost-effectiveness ratio and incremental cost-effectiveness ratio will be used to assess the difference in cost effectiveness of the two materials at 6, 12, and 24 months after surgery. The trial hopes to prove that compared with titanium mesh, the use of polyetheretherketone for skull repair has a better repair effect for 2 years, a lower incidence of adverse events, better biocompatibility, and obvious advantages in long-term efficacy and security. This study was registered with the Chinese Clinical Trial Registry on February 27, 2021 (registration number: ChiCTR2100043703). Study protocol version is 1.0. [ABSTRACT FROM AUTHOR]