Background <p>The aim of this study was to evaluate and compare complication rates and clinical outcomes associated with smooth and perforated polyetheretherketone (PEEK) implants used in cranioplasty.</p> Methods <p>A retrospective analysis of 94 patients who underwent cranioplasty with either smooth (<i>n</i> = 45) or perforated (<i>n</i> = 49) PEEK implants over a five-year period was conducted. Patient demographics, comorbidities, reasons for initial craniectomy, time interval between craniectomy and cranioplasty, postoperative complications, hospital stays, and rates of revision surgeries were analyzed. Multivariate logistic regression was used to control for confounding factors.</p> Results <p>No statistically significant differences were observed in demographic characteristics, reasons for initial craniectomy, or median time to cranioplasty between groups. Complication rates including wound complications, infections, ventriculoperitoneal (VP) shunt placements, significant fluid collections, return to surgery, and implant removals were comparable between groups, though trends suggested potential increases in wound complications (17.8% vs. 8.2%, <i>p</i> = 0.11) and infections (17.8% vs. 8.2%, <i>p</i> = 0.22) in the smooth implant group. Interaction analysis indicated a significant reduction in significant fluid collections with smooth implants in trauma patients (<i>p</i> = 0.045). Importantly, a rare and previously unreported case of malignant cerebral edema following smooth PEEK implant placement was documented.</p> Conclusions <p>Although no statistically significant differences were found, the identified trends toward increased complications with smooth implants and the novel finding of malignant cerebral edema highlight the importance of implant surface characteristics. Further prospective randomized studies are needed to clarify these preliminary observations and guide clinical decision-making in cranioplasty procedures.</p>