Objective:To introduce the design, manufacture and clinical application of the custom-made temporomandibular joint (TMJ)-skull base combined prosthesis and evaluate its safety, effectiveness and accuracy.Methods:The patients diagnosed with the TMJ-skull base lesion in Department of Oral Surgery, Shanghai Ninth People′s Hospital from October 2016 to November 2020 were recruited in this study. The maxillofacial CT data for all the patients were obtained and transformed into the Mimics 18.0 software preoperatively. The custom-made TMJ-skull base combined prosthesis, included four components, was designed based on the anatomy, stress distribution and movement of the TMJ and skull base, and fabricated by three-dimensional printing and 5-axis milling technologies. The TMJ-skull base lesion was excised completely with the help of digital templates from modified preauricular and/or post and submandibular incisions. The combined prosthesis were implanted and fixed after the lesion resection. The examinations including general situation, cranio-maxillofacial structure and function were taken during and after surgery to assess its using effect.Results:Ten patients [6 females and 4 males, (43.2±13.6) years old] were included and all prostheses were positioned accurately and fixed excellently. After (29.4±17.3) months follow-up, the occlusion relationship was stable and no adverse symptoms such as dizziness, headache, meningeal irritation and permanent facial nerve injury occurred. The pain, diet, mandibular movement function, lateral movement to diseased side and mouth opening had significant improvements. The forward movement and lateral movement to normal side were not improved significantly. There were no prosthesis displacement, loosening and fracture in X-ray and CT postoperatively. With the pre and postoperative craniomaxillofacial model merging, the maximal implanted error was (0.52±0.17) mm for fossa and condyle and (1.62±0.26) mm for skull base and mandibular handle in surface deviation analysis.Conclusions:The custom-made TMJ-skull base combined prosthesis with customized design and 3D printing fabrication is safe, effective and precise in clinical application.