Symmetry is representative of aesthetics and health in all kinds of vertebrates, especially the human face. Therefore, to automatically locate the appropriate symmetry plane is crucial. The aim of this study was to develop an automatic and reliable method to determine the symmetry plane of the maxillofacial region. We compared the proposed method of determining the symmetry plane by assessing landmark-based and surface-based methods by way of quantitative symmetry assessments. Statistical analysis was applied to evaluate whether significant difference existed among these three kinds of symmetry planes. Twenty cases who had a diagnosis of severe facial asymmetry were evaluated retrospectively. The results showed that searching for the symmetry plane using a voxel-based method, named the optimal symmetry plane (OSP), achieved the most representative symmetry according to the outcomes of the trials. The OSP was significantly more symmetrical than the other two planes, as determined by other methods. The paired-voxel computation method proposed in this research is a robust and reliable method for identifying the unique symmetry plane for patients with severe facial asymmetry. Symmetry is of crucial significance for all kinds of vertebrates, including its clinical implications for surgical planning in orthognathic surgery.