INTRODUCTION: Pirfenidone is a non-peptide synthetic low molecular weight substance with anti-inflammatory, antioxidant and antifibrotic effects. Its positive effects have been shown on ischemia-reperfusion injury in various tissues such as testis, kidney, liver, lung and small intestine. Our aim is to investigate the effects of Pirfenidone on ischemia-reperfusion injury in skin flaps. METHODS: Eighteen Wistar male rats were divided randomly into three groups: Sham, Ischemia-Reperfusion (IR) and Pirfenidone plus Ischemia-Reperfusion (IR+Pirf). The epigastric island flap was elevated and returned to its place in the Sham group. In the second group (IR), the flap was elevated, and flap perfusion was interrupted with an avascular clamp for eight hours. In the third group (IR+Pirf), 300 mg/kg Pirfenidone was given orally before ischemia. Tissue samples were taken to evaluate biochemical substances (1st day) and histopathologic examination (7th day). On the seventh day, standardized photographs were taken to calculate the viable areas of the flap and all animals were sacrificed. Results: Tissue MPO levels were statistically higher in the IR+Pirf group than in the Sham and IR groups (p=0.006). Tissue MDA levels were statistically higher in the IR+Pirf group than in the IR group (p=0.026). The lymphocyte count was lower in the Sham group than in the IR and IR+Pirf groups (p=0.002). The reepithelization ratio was higher in the IR+Pirf group than in the IR and Sham groups p=0.010). Flap survival areas showed no significant difference between groups (p=0.194). DISCUSSION AND CONCLUSION: As a conclusion, single dose treatment of Pirfenidone in rat skin flap ischemia-reperfusion model enhanced significantly re-epithelization and has no significant effect on flap survival.