Cranioplasty is a surgery in which a prosthesis must be anchored on skull bone to repair a defect. One of the most used materials is the titanium. However, titanium prostheses could be made using the incremental sheet forming (ISF). Since titanium and bone are characterized by different Young modules, a detailed design of anchoring system is required to avoid cranial rupture. Aim of this study was to present a design procedure in order to identify the optimal anchoring system in case of craniofacial prostheses made with ISF. In detail, an optimization process and a predictive model for bone stress were used, choosing the numerical outputs of different FEM analyses as input data. The results indicate that our predictive and optimization models are accurate and, so, that this procedure could be very helpful for the prosthesis design, as demonstrated by the application of the procedure to a real case study.