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Background: The customized prosthesis is a new method for the reconstruction of large mandibular defects. The ability of dental rehabilitation to improve masticatory functions while maintaining the aesthetics of the main anatomy of the patient’s jaw. But the most important problem with all custom prosthesis is the poor performance of screw fixation strength the connections at the bone-plate interface. Materials and Methods: This study was performed to investigate the effect of the number and layout of screws to improve the strength of the bone–prosthesis interface. Due to the inherent variability of input parameters, Analysis of the biomechanical performance of screw fixation strength, a probabilistic finite element method approach has been used. Random input parameters include mechanical properties of the cortical bone, cancellous bone, titanium alloy (Ti6Al4V), and bite force. The layout of the screws was designed in 6 models. Criteria for evaluating the biomechanical performance of screw fixation strength include maximum stress and strain of von Mises cortical bone around the screws. The Monte-Carlo method was used for finite element simulation. Results: The most critical screw in all models is screw No.1, which by increasing the number of screws and correcting the layout shape, the values of maximum stress and strain in the bone around screw No.1 has decreased by 26.7% and 46.3%, respectively, and increased the reliability of the screw connection performance by 25% and 28%, respectively. Conclusion: Finally, in the reconstruction of a large lateral mandibular defect by the customized prosthesis, the strength of the prosthesis to connect to the remaining mandible bone can be improved by increasing the number and modifying the layout of the screws. Keywords: Mandible reconstruction; Customized prosthesis; Probabilistic finite element method; Reliability.