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An optimal design method for the main bearing of a tunnel boring machine is proposed. In this method, the fatigue life is used as the objective function. Structural parameters, including clearance, are considered as design variables. First, a quasi-static model of the main bearing and a calculation model of the fatigue life are established. The correctness of the theoretical method is verified by comparing it with the calculation results of the finite element method. Next, the influence of clearance on the load-carrying performance under external loads is analyzed. There is an optimal negative clearance for the axial loaded and radial rows. With the increase in the external loads, the optimal negative clearance gradually decreases. The variation laws of the load-carrying performance for the axial loaded and supporting rows affected by axial clearance mainly depend on the bias load degree of the main bearing. Finally, based on the optimal design model of the main bearing, the optimal internal structure is obtained using the genetic algorithm. The optimized fatigue life is improved by 92.2%. The load-carrying performance of the optimal main bearing has also been significantly enhanced compared to the initial design. Therefore, the proposed optimization method provides a practical approach to the main bearing design.