OBJECTIVE: One of the most important factors that adversely affects the outcome of peripheral nerve surgery is the formation of epineural and extraneural scar tissue after surgery. Many surgical methods and pharmacological and chemical agents have been used to prevent the formation of epineural scar tissue, but satisfactory results have not been achieved in clinical applications. The purpose of this study was to investigate the combined effect of fat graft and platelet-rich fibrin on the formation of epineural scar tissue and on nerve healing in the mature rat model. METHODS: A total of 24 female Sprague-Dawley rats were used. A circumferential segment of epineurium was excised from both bilateral sciatic nerves. The epineurectomized right nerve segment was wrapped with a combination of fat graft and platelet-rich fibrin (experimental group), while the left nerve segment did not receive any surgical procedure other than the epineurectomy (sham group). Notably, 12 randomly selected rats were sacrificed in the fourth week for histopathological examination of early results. The other 12 rats were sacrificed in the eighth week for late results. RESULTS: The formation of fibrosis, inflammation, and myelin degeneration were less common in the experimental group, while nerve regeneration was found to be higher at both 4 and 8 weeks. CONCLUSION: The intraoperative application of a combination of fat graft and platelet-rich fibrin appears to be effective on nerve healing after surgery at both the early and late periods.