Safety plays a key role in human–robot interactions in collaborative robot (cobot) applications. This paper provides a general procedure to guarantee safe workstations allowing human operations, robot contributions, the dynamical environment, and time-variant objects in a set of collaborative robotic tasks. The proposed methodology focuses on the contribution and the mapping of reference frames. Multiple reference frame representation agents are defined at the same time by considering egocentric, allocentric, and route-centric perspectives. The agents are processed to provide a minimal and effective assessment of the ongoing human–robot interactions. The proposed formulation is based on the generalization and proper synthesis of multiple cooperating reference frame agents at the same time. Accordingly, it is possible to achieve a real-time assessment of the safety-related implications through the implementation and fast calculation of proper safety-related quantitative indices. This allows us to define and promptly regulate the controlling parameters of the involved cobot without velocity limitations that are recognized as the main disadvantage. A set of experiments has been realized and investigated to demonstrate the feasibility and effectiveness of the research by using a seven-DOF anthropomorphic arm in combination with a psychometric test. The acquired results agree with the current literature in terms of the kinematic, position, and velocity aspects; use measurement methods based on tests provided to the operator; and introduce novel features of work cell arranging, including the use of virtual instrumentation. Finally, the associated analytical–topological treatments have enabled the development of a safe and comfortable measure to the human–robot relation with satisfactory experimental results compared to previous research. Nevertheless, the robot posture, human perception, and learning technologies would have to apply research from multidisciplinary fields such as psychology, gesture, communication, and social sciences in order to be prepared for positioning in real-world applications that offer new challenges for cobot applications.