The stiffness modeling for a compliant parallel manipulator (CPM) is very important since it provides a basis for the characterization of static, modal, and dynamic behavior of the CPM. This paper presents the stiffness modeling of a three-prismatic-universal-universal (3-PUU) CPM with orthogonally mounted actuators, that is designed to provide three spatial translational DOF for nano-scale manipulation. Considering the compliance of each compliant element, the analytical stiffness model for a spatial CPM is established by a straightforward approach, which is then applied to stiffness modeling of the 3-PUU CPM. In addition, the finite element analysis is carried out to validate the developed model, and as a further application, the influence of architectural parameters on stiffness factors are derived based on the stiffness model, which is valuable for a cost-effective design of the CPM.