Abstract Objective Cranioplasty is routinely performed in neurosurgery. One of its underestimated problems is the high postoperative complication rate of up to 40%. Due to the lack of good prospective studies and the low number of patients (5–20 each year) receiving alloplastic materials, decisions in favor or against a certain material are based on subjective empirical or eco-nomic reasons. The main goal of this first prospective, randomized multicenter study in Germany of custom-made titanium and hydroxyapatite (HA) implants was to compare lo-cal and systemic infections related to the implant within the first six months after implanta-tion. Secondary objectives included comparing reoperation rates, the complication rate, clinical and neurological outcome, and health-related quality of life. Methods The study included patient screening and randomization 6–8 weeks before operation, pre-, intra and postoperative documentation until discharge, and postoperative follow-ups after one and six months. Approval for the study was obtained from the local ethics committee. The study design was published on www.clinicaltrials.gov. Results A total of 52 patients were included in the study. The rate of local, implant associated wound infection in the HA group was 2 out of 26 (7.7%) patients and 5 out of 24 (20.8%) patients in the titanium group (p=0.407 n.s.). Systemic inflammation within six months after operation affected none of the patients in the HA group and 4 out of 24 (37.5%) pa-tients in the titanium group (p=0.107 n.s.). In both groups, 7 patients had to be reoperated after the six-month follow-up (26.9% in the HA group and 29.2% in the titanium group; n.s.). Re-surgery with explantation was necessary in 3 patients in each group (11.5% in the HA group and 12.5% in the titanium group; n.s.). The results demonstrated a significantly higher number of epidural hematomas in the HA group compared to none in the titanium group. Altogether, 46 AE were measured in 27 patients (54%). An improvement of the neurologi-cal outcome after six months was experienced by 43% of the patients in the HA group and 26.3% in the titanium group (p=0.709 n.s.). Conclusion The study emphasizes that cranioplasty is a high-risk intervention. Compared to tita-nium, HA shows a benefit in the infection rate and the neurological outcome, but has at the same time a higher postoperative risk for epidural hematoma. Depending on the individual conditions both materials have their place in future therapy of cranioplasty.