PURPOSE: Peripheral nerve injuries can lead to lasting functional impairments, impacting movement and quality of life. FK-506, a widely used immunosuppressant, has demonstrated potential in promoting nerve regeneration in addition to its immunosuppressive effects. This study investigates the use of a local reservoir flap to deliver FK-506 directly to the nerve injury site, aiming to enhance nerve regeneration while minimizing systemic immunosuppression. MATERIALS AND METHODS: Sciatic nerve injuries were surgically induced in 24 rats, which were divided into control, 0.5 mg/kg FK-506 (Exp 1), and 2.0 mg/kg FK-506 (Exp 2) groups. A superficial inferior epigastric artery flap served as a reservoir for FK-506, allowing direct delivery to the injury site. FK-506 was administered intermittently over a 4-week period. Outcomes included the Sciatic Functional Index (SFI), muscle recovery (width and weight), nerve morphology, expression of neurogenic markers such as GDNF, immune cell counts, and body weight. RESULTS: Exp 1 (0.5 mg/kg) demonstrated significant improvements in SFI, GDNF expression, and muscle width compared to the control and high-dose groups. These findings suggest that FK-506 administration via a reservoir flap, particularly at a lower dose, supports effective nerve regeneration. Additionally, FK-506 treatment did not result in significant changes in immune cell profiles or body weight, indicating minimal systemic effects. CONCLUSION: Localized FK-506 administration via a reservoir flap effectively enhances peripheral nerve regeneration and minimizes systemic immunosuppression, making it a promising approach for clinical application in treating peripheral nerve injuries.