In this research activity, a new methodology for the synthesis of hand exoskeleton mechanisms has been developed and validated through real prototypes. The innovative methodology is based on a new parallel mechanism and has been tested by building a robotic assistive device for hand opening disabilities applied to real cases. The studied robotic orthosis is designed to be a low-cost, adaptable and portable hand exoskeletons to assist people with hand opening disabilities in their activities of daily livings. As regards the methodology for the synthesis of hand exoskeleton mechanism, the authors propose to use a motion capture system to acquire the real hand phalanx trajectories and the geometrical characteristics of the patient’s hand, and to use optimization algorithms to properly defines the novel kinematic mechanism that better fits the finger trajectories. The preliminary testing phase of the prototype on a single patient is concluded; currently, through the collaboration with an Italian rehabilitation center, a group of patients are testing the proposed HES methodology.