Spot weld layout design for body structures is of practical significance to both manufacturing cost control and performance improvement in the automotive industry. In this work, by using a typical thin-walled double-hat section beam as a proxy, a parametric study was first carried out to reveal the effects of spot weld layout design on the structural performances under both static and impact loading conditions. To overcome the limitation of traditional uniformly spaced spot weld configuration, an innovative size optimization based procedure was proposed for the spot weld layout design of automotive structures with irregular spacings. In this procedure, sampling points that satisfy both equality and inequality constraints are obtained by introducing the mixture design of experiment method. The leave-one-out cross validation strategy is used to bring the training samples into full play in building surrogate models for structural analyses with high accuracy. Moreover, the NSGA-II is incorporated to search the Pareto front of the multiobjective optimization problem. Application of the proposed procedure on the thin-walled double-hat beam resulted in 33.3% spot welds reduction from the uniformly spaced baseline design, without weakening the structural static and NVH performances by more than 3%. The reliability and effectiveness of the proposed procedure is thus proved.