The foundation of LiShuiGou Aqueduct of ShiMen Reservoir is composed of long-short and large diameter piles, with great diameter and length differences between these new and old piles. Numerical simulation of the FEM software ADINA and the orthogonal experimental design theory are applied to explore the sensitivity of long-short pile foundation settlement, under different pile length, pile diameter, pile space, and soil constitutive model, with foundation settlement as the evaluation index. The results show that the descending order of the sensitivity of four factors is: pile length > pile diameter > pile space > soil constitutive mode. Some scientific and rational approaches and basis are consequently provided to explore the most effective reinforcement measures and design method for long-short and large diameter piles.