Abstract: The measured data of foundations of high-rise buildings indicate that there are two shortcomings for those pile-box and pile-raft foundations designed by using the traditional design concept. One is disk-shape settlement distribution, which may result in the significant secondary forces in the super structure, and the other is the saddle-shape reaction distribution, which may result in the increase of punch force and moment in foundation slabs. In view of superstructure-soil-foundation interaction effect, the optimization design method for pile foundation and soil stiffness is put forward based on the loads, geological characteristics and superstructure layout by analyzing the field experimental results. The optimization design method adopts strengthening and reducing settlement, coupling hardness with softness, local balances, entirety harmony to realize differential settlement, cap internal force(foundation) and minimized resources consumption. Based on the conceptual design, the analysis of the interaction of superstructure-foundation-pile-soil helps to further optimize pile arrangement and reinforcements in the slab. An engineering case is taken as an example to analyze and interpret the application of strengthening index and avianizing index in the optimization design of pile foundation stiffness to reduce differential settlement.