Object Decompressive craniectomy is an established procedure to lower intracranial pressure. Therefore, cranioplasty remains a necessity in neurosurgery as well. If the patient's own bone flap is not available, the surgeon can choose between various alloplast grafts. A review of the literature proves that 4–13.8% of polymethylmethacrylate plates and 2.6–10% of hydroxyapatite-based implants require replacement. In this retrospective study of large skull defects, the authors compared computer-assisted design/computer-assisted modeled (CAD/CAM) titanium implants for cranioplasty with other frequently used materials described in literature. Methods Twenty-six patients underwent cranioplasty with CAD/CAM titanium implants (mean diameter 112 mm). With the aid of visual analog scales, the patients' pain and cosmesis were evaluated 6–12 years (mean 8.1 years) after insertion of the implants. Results None of the implants had to be removed. Of all patients, 68% declared their outcomes as excellent, 24% as good, 0.8% as fair, and 0% as poor. There was no resulting pain in 84% of the patients, and 88% were satisfied with the cosmetic result, noting > 75 mm on the visual analog scale of cosmesis. All patients would have chosen cranioplasty again, stating an improvement in their quality of life by the calvarial reconstruction. Nevertheless, follow-up images obtained in 4 patients undergoing removal of meningiomas was only suboptimal. Conclusions With the aid of CAD technology, all currently used alloplastic materials are suited even for large skull defect cranioplasty. Analysis of the authors' data and the literature shows that cranioplasty with CAD/CAM titanium implants provides the lowest rate of complications, reasonable costs, and acceptable postoperative imaging. Polymethylmethacrylate is suited for primary cranioplasty or for long-term follow-up imaging of tumors. Titanium implants seem to be the material of choice for secondary cranioplasty of large skull defects resulting from decompressive craniectomy after trauma or infarction. Expensive HA-based ceramics show no obvious advantage over titanium or PMMA.