The aim of the work is to perform a comparative study of the compression system for a polymer electrolyte membrane (PEM) fuel cell. This study wishes also to address some key-features on the suitability of different compressors with respect to the main system design issues (e.g. energy balance, system performance and control). According to the technologies currently considered as being able to meet fuel cell system requirements, sliding vane, twin-screw and centrifugal compressors have been studied. The analysis has been performed making use of a modeling approach based on both thermodynamic description of the plant and synthesis of experimental efficiency data. Altogether, the results indicate that the centrifugal compressor should be preferred due to its higher efficiency as compared to the other compressors analyzed. Nevertheless, specific applications (e.g automotive field) may redirect the selection of the optimal compression device towards the other typologies, because of the highly fluctuating power demands and the issues associated with the narrow centrifugal compressor operation range.