Aimed to reduce the deformation of workpiece-fixture system, one fixture layout and clamping force optimal method is constructed in this paper. Firstly, system stiffness matrix is built by Finite Element Method (FEM), and one matrix size reducing method is proposed to avoid the high computing time cost of solving FEM balance equation. Secondly, one clamping force optimization method which should be called after fixture layout is generated during every step of optimization algorithm is presented to lessen calling times of FEM solving process and save running time. And then based on these, one fixture layout and clamping force optimization algorithm is constructed using genetic algorithm (GA). At the end of this paper, numeral examples are taken to verify the validity and usability of the methods.