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Manufacturing ergonomics refers to the application of ergonomic principles and human factors analysis to the design of manufacturing tasks with the final aim to optimize the workers’ wellbeing and guarantee the expected process performance. Traditional design approaches are based on the observation of individual workers performing their jobs, the detection of unnatural postures (e.g., bending, twisting, overextending, rotating), and the definition of late corrective actions according to ergonomic guidelines. Recently, computer-integrated simulations based on virtual prototypes and digital human models (DHMs) can be used to assess manufacturing ergonomics on virtual manikins operating in digital workplaces. Such simulations allow validating different design alternatives and optimizing the workstation design before the creation, and pave the way to a new approach to manufacturing system design. The present paper aims at comparing different computer-integrated set-ups to support the design of human-centred manufacturing workstations. It defines a protocol analysis to support workstation design by analysing both physical and cognitive aspects, and applies the protocol within different digital set-ups. In particular, the study investigates a 2D desktop set-up using standardized DHMs and a 3D immersive mixed reality set-up based on motion capture of real workers’ acting into a mixed environment, comparing them with the traditional approach. An industrial case study focusing on design optimization of a manufacturing workstation in the energy industry is used to test the effectiveness of the two digital set-ups for the definition of re-design actions.