Objective: This study presents an innovative articular fossa prosthesis generated by the envelope surface of condyle movement, and compares its mandible movements, muscle activities, and joint reaction forces with two temporomandibular joint (TMJ) prostheses using multibody musculoskeletal simulation.Methods: A healthy 23-year-old female was recruited for this study. Cone-beam computed tomographic (CBCT) was performed to reconstruct the mandibular bone geometry. A customized TMJ fossa prosthesis was designed based on the subject-specific envelope surface of condyle movement (ESCM). Mandibular kinematics and jaw-closing muscle electromyography (EMG) were simultaneously recorded during maximum jaw opening-closing movements. To validate our prosthesis design, a mandibular musculoskeletal model was established using flexible multibody dynamics and the obtained kinematics and EMG data. The Biomet fossa prosthesis and the ellipsoidal fossa prosthesis designed by imitating the lower limb prostheses were used for comparison. Simulations were performed to analyze the effects of different fossa prostheses on jaw opening-closing motions, mandibular muscle activation, and contact forces.Results: The maximum opening displacement for the envelope-based fossa prosthesis was greater than those for Biomet and ellipsoidal prostheses (36 mm, 35 mm, and 33 mm, respectively). The mandibular musculoskeletal model with ellipsoidal prosthesis led to dislocation near maximal jaw opening. Compared to Biomet, the envelope-based fossa reduced the digastric and lateral pterygoid activation at maximal jaw opening. It also reduced the maximal resistance to condylar sliding on the intact side by 63.2 N.Conclusion: A customized TMJ fossa prosthesis was successfully developed using the ESCM concept. Our study of musculoskeletal multibody modeling has highlighted its advantages and potential. The artificial fossa design successfully achieved a wider condylar range of motion. It also reduced the activation of jaw opening muscles on the affected side and resistance on the intact side. This study showed that an ESCM-based approach may be useful for optimizing TMJ fossa prostheses design.