Titanium prostheses are artificial components used during cranioplasty, which can be made with the Incremental Sheet Forming (ISF). To repair the craniofacial defects, the implant must be fixed to the skull, so an adequate anchoring system is necessary. Because there are no specific guidelines regarding this system, the aim of this study was to present a methodology for the identification of the optimal screw shank diameter and the overlap length, considering different damage areas and accidental external loads. In this method, a numerical model for structural analysis, a statistical approach and a metamodeling technique were coupled. The results demonstrate that this methodology can be used as a decision support tool in the titanium prostheses design, ensuring the best anchorage.