Deriving the optimal layout of fixture elements is critical to minimizing the impact of fixture–workpiece deformation on machined feature error. Various optimization methods for solving this problem have been reported. Unfortunately no investigation has been executed to compare their relative performance. This paper presents the methodology and results of an extensive investigation into the relative effectiveness of the main elements of these competing methods. All methods were tested over a broad range of conditions. Performance measures that were tracked included solution quality, solution repeatability, and computation time. The results of this investigation show that the best overall performance is provided by optimization methods that use both the genetic algorithm and continuous interpolation for the distribution of boundary conditions.