This paper proposes a direct three-dimensional (3D) numerical method in time domain for seismic soil-structure interaction (SSI) analysis of spatial grid structure. First, a finite element model including soil, foundation and typical spatial grid structure is developed. Then, the precisions of equivalent viscous-spring artificial boundary element (VSABE) and size effect of site soil region are discussed. Finally, under different site types, time history analyses for models with or without considering SSI effect are implemented respectively under horizontal seismic excitation. The results show that VSABE has the same precision as infinite element boundary and plane size of truncated soil region can be five times of structure plane size for SSI analysis of spatial grid structure. Moreover, except for hard site, it is shown that horizontal acceleration and displacement of spatial grid roof increases substantially when SSI effect is considered. Therefore, it is suggested that SSI influence should be taken into account in engineering design of spatial grid structure.