The European Parliament has imposed to reduce by 2030 whole HFC emissions by at least two-thirds with respect to 2014 levels. With the aim of contributing to determine the energy and environmental advantages of refrigerants alternative to R-410A, this paper reports the results of a numerical study focused on an HVAC system coupled to a residential building and based on a reversible electric heat pump. In particular, two heat pump typologies are considered: an air-source and a ground-source heat pump, both operating with the two refrigerants R-410A and R-454B. The environmental performance of the studied system is assessed by means of the TEWI (total equivalent warming impact) index. The adoption of R-454B involves a slight decrease (2–3%) in the overall annual energy performance of the system with respect to the use of R-410A. On the other hand, the working fluid R-454B guarantees a marked decrease in the TEWI indicator. Indeed, considering the current Italian emission factor of electricity taken from the grid, the total emissions over the entire heat pump operating life drop by about 25% and can decrease by up to 89% in perspective, following the current reduction trend of the emission factor.