Background and objectives <p>Duraplasty is commonly required when primary dural closure is not feasible during cranial surgery. Although both autologous and synthetic dural substitutes are widely used, high-quality prospective data comparing their early postoperative safety remain limited. This study aimed to compare early postoperative complication rates following cranial duraplasty using autologous pericranium versus high-density polypropylene (G-Patch).</p> Methods <p>This prospective randomized comparative study enrolled 121 consecutive patients undergoing cranial duraplasty at a tertiary care center between January and December 2021. Following exclusion of patients who died within 30&#xa0;days postoperatively, 100 patients (50 per group) were included in the final analysis. Patients were allocated to receive either autologous pericranium (<i>n</i> = 50) or high-density polypropylene (G-Patch) (<i>n</i> = 50) using a standardized surgical technique. The primary outcome was the occurrence of any postoperative complication within 30&#xa0;days, including cerebrospinal fluid leak, wound infection, and subdural empyema. Effect estimates were expressed as odds ratios (OR) with 95% confidence intervals (CI), and a limited adjusted analysis was performed as a sensitivity assessment.</p> Results <p>Traumatic brain injury and intracranial space-occupying lesions were the most common indications for surgery. Most patients in both groups had an uneventful postoperative course. Early postoperative complications occurred in 26% of patients in the synthetic graft group and 12% in the autologous group. The unadjusted odds ratio for any complication with synthetic graft use was 2.58 (95% CI: 0.88–7.54; <i>p</i> = 0.08). After adjustment for primary diagnosis, graft type remained a non-significant predictor of complications. No consistent associations were observed between postoperative complications and comorbidities or substance use in exploratory analyses.</p> Conclusion <p>In this prospective randomized cohort, both autologous pericranium and high-density polypropylene demonstrated acceptable short-term safety profiles. However, given the limited sample size, imbalance in underlying diagnoses, and short follow-up, these findings should be interpreted with caution and should not be considered evidence of equivalence between graft materials. Further studies with larger sample sizes, stratified analyses, and long-term outcomes are required.</p> Trial registration <p>This investigator-initiated pragmatic randomized study was not prospectively registered in a clinical trial registry.</p>