For the soils in sloping ground, the effect of static shear stress must be considered to evaluate the cyclic behaviors of soils when subjected to seismic loading. This study aims to reveal the effect of both static shear stress magnitude and direction on the cyclic behaviors of the medium-dense sand based on a series of multi-directional cyclic simple shear tests. It is found that the effect of static shear stress on the liquefaction resistance of the medium-dense sand is detrimental in both parallel and perpendicular loading modes. The detrimental effect is more pronounced in parallel loading mode. Under the perpendicular loading mode, the full liquefaction of the specimens cannot be reached. The deformation pattern of the specimens is cyclic mobility along the cyclic loading direction, and plastic strain accumulation along the static stress direction. A modified pore pressure prediction model with two fitting parameters is further proposed to incorporate the effect of static shear stress.