Introduction:The use of semi-synthetic dural substitutes in cranial surgery has garnered attention due to its potential in reducing complications, particularly Cerebrospinal Fluid (CSF) leakage. However, there is a lack of extensive research, especially in the form of randomized studies, to validate its efficacy and safety. Methods: Our study was divided into two parts: a retrospective analysis of 30 patients who received semi-synthetic dural replacements from December 2022 to March 2023, and a prospective study of another 30 patients from March 2023 to September 2023. The inclusion criteria were patients over 18 undergoing neurosurgical procedures requiring dural replacement. The primary outcome measured was the rate of CSF leakages, with secondary outcomes including clinical and radiographic parameters to assess signs of infection or inflammation. Results: Both the retrospective and prospective studies successfully included 30 patients each, with no adverse events reported in either group. No evidence of CSF leakage or inflammation was observed in the postoperative period. The average age of patients was 63.2 years in the retrospective group and 61.2 years in the prospective group, with a balanced distribution of male and female patients. Discussion: The results indicate that semi-synthetic dural replacement is a safe and effective option in cranial surgery, aligning with findings from other studies in the field. However, the variability in CSF leakage rates in existing literature underscores the need for larger, randomized studies for a more definitive conclusion. Conclusion: Our study supports the use of semi-synthetic dural substitutes as a safe and low-risk option in neurosurgery. While our results are encouraging, further large-scale randomized studies are necessary to conclusively determine its effectiveness in preventing CSF leakage.