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To decarbonize Europe achieving almost zero emissions in 2050, more stringent regulations are going to be applied. Particularly, Europe is investing in the emissions’ re-duction of buildings (existing and new ones), and strong improvements in energy performance of building are expected according to novel energy performance of building directive (at last phase of negotiation). At the same time, the production and use of fluorinated gases will be further reduced with the novel F-Gas regulation (under Parliament approval). New F-Gas will affect remarkably the small size, air-to-air split systems for air-conditioning, since no fluorinated gases will be used after 2035, forcing manufacturers to the use of natural refrigerants. Being propane the most efficient among the non-toxic natural refrigerants, less refrigerant would be charged into systems according to current safety standards: this would potentially reduce the heat transfer surfaces and, consequently, for the same capacity, the energy efficiency or, for the same efficiency, the capacity would decrease. In this paper, some scenario analyses, complying with actual and future plausible dispositions, are presented, in order to showing the margins for de-sign and commenting criticalities. In particular, the optimal design options are proposed for different fluids, in terms of costs vs energy performance, under representative cases, in terms of weather conditions and building types in Italy (existing ones and new ones respecting high-efficiency standards, trying to meet the requirements of hypothesized national law following the draft of the novel EPBD).