Objective: This study investigated the effect of topical 5-Fluorouracil (5-FU) application on the epineural scar tissue, which has a negative impact on the outcome after a peripheral nerve surgery, and whether the application of two doses of 5-FU would change the outcome.     Materials and Methods: The study involved 72 3-month-old female Spradue-Dawey rats weighing 250-300 g each. After the experimental animals were observed for a week to make certain that they were healthy, they were randomly divided into 3 main groups; Group A: skin incision + epineurotomy + isotonic (n=24), Group B: skin incision + epineurotomy + single dose of 5-FU (n=24) and Group C: skin incision + epineurotomy + two doses of 5-FU (n=24). Each group was divided into 2 subgroups based on the weeks in which they were examined. The two subgroups in each of the three groups were made subject to a walking test, and macroscopic and histopathological examinations at Week 4 and Week 8.      Results: An evaluation of the macroscopic results showed that there was a statistically significant difference between Group A and Group C in sciatic nerve adhesion and severability of its branches. We obtained better results in Group C,  when compared  with the results obtained in Group A.             Conclusion: We demonstrated in our study that 5-FU had a positive effect on the scar tissue developed around the epineurectomized nerve. This positive effect was also reflected in the nerve’s functional capacity, and a second dose of 5-FU application further improved this effect.