The heat driven ejector systems represent a promising alternative to produce cooling effect using low-grade temperature sources, promoting the use of the renewable sources in the air-conditioning sector. The working fluids significantly influence the system performance as well as the environmental impact. The recent F-Gas European Regulation will limit the use of refrigerants with high GWP, as HFC ones. In this paper, an optimization process for the selection of the optimal working fluid was proposed. Vapor generator temperature, evaporation temperature and condensation temperature were considered as decision variables. Some limits are considered in order to take into account the operating range of the liquid pump and of the ejector. The following two parameters are selected as objective functions: the coefficient of performance of the system and the total heat exchanger area for unit of heat power input at the generator. This work could give some indications about the choice of the appropriate working fluids, considering criteria of performance enhancement as well as components size reduction.