A proper design of the mooring systems for Wave Energy Converters (WECs) requires an accurate investigation of both operating and extreme wave conditions. A careful analysis of these systems is required to design a mooring configuration that ensures station keeping, reliability, maintainability, and low costs, without affecting the WEC dynamics. In this context, an experimental campaign on a 1:20 scaled prototype of the ISWEC (Inertial Sea Wave Energy Converter), focusing on the influence of the mooring layout on loads in extreme wave conditions, is presented and discussed. Two mooring configurations composed of multiple slack catenaries with sub-surface buoys, with or without clump-weights, have been designed and investigated experimentally. Tests in regular, irregular, and extreme waves for a moored model of the ISWEC device have been performed at the University of Naples Federico II. The aim is to identify a mooring solution that could guarantee both correct operation of the device and load carrying in extreme sea conditions. Pitch motion and loads in the rotational joint have been considered as indicators of the device hydrodynamic behavior and mooring configuration impact on the WEC.