One of the main advantages of using Steel Plate Shear Panels (SPSPs) as lateral load resisting system is the ability to create openings at desired locations within the panels for access and architectural requirements. Stiffeners are used on the infill plate in order to achieve better structural performance and optimum utilization of the system's linear and nonlinear capabilities. Three 1/3rd scale specimens with two openings and with different separations, subjected to cyclic loads, were used to study the structural behavior of SPSPs. The Plate-Frame Interaction (PFI) model, enhanced with additional refinements, was used in theoretical studies to determine the shear stiffness and ultimate shear strength of the SPSPs. The results of the theoretical studies were compared with the experimental and numerical methods. The outcome showed that the new PFI theory predicted the structural behavior of SPSPs with a good agreement.