Despite the development of computer-based methods, cranial reconstruction of very large skull defects remains a challenge particularly if the damage affects the midsagittal region hampering the usage of mirror imaging techniques. This pilot study aims to deliver a new method that goes beyond mirror imaging, giving the possibility to reconstruct crania characterized by large missing areas, which might be useful in the fields of paleoanthropology, bioarcheology, and forensics. We test the accuracy of digital reconstructions in cases where two-thirds or more of a human cranium were missing. A three-dimensional (3D) virtual model of a human cranium was virtually damaged twice to compare two destruction-reconstruction scenarios. In the first case, a small fraction of the midsagittal region was still preserved, allowing the application of mirror imaging techniques. In the second case, the damage affected the complete midsagittal region, which demands a new approach to estimate the position of the midsagittal plane. Reconstructions were carried out using CT scans from a sample of modern humans (12 males and 13 females), to which 3D digital modeling techniques and geometric morphometric methods were applied. As expected, the second simulation showed a larger variability than the first one, which underlines the fact that the individual midsagittal plane is of course preferable in order to minimize the reconstruction error. However, in both simulations the Procrustes mean shape was an effective reference for the reconstruction of the entire cranium, producing models that showed a remarkably low error of about 3 mm, given the extent of missing data. Anat Rec, 296:745–758, 2013. © 2013 Wiley Periodicals, Inc.