Organic Rankine Cycles (ORCs) are experiencing a growing interest due to their ability to generate electricity from residual low waste heat sources. HFC-245fa is a representative working fluid for ORC applications, but it has recently been phased-out in new equipment because of its high global warming potential (GWP). In this work, the soft-SAFT molecular-based equation of state is used to evaluate the capacity of nine promising low-GWP hydrofluoroethers (HFEs) as alternative working fluids in ORC applications using different key performance indicators focused on energy efficiency and service fluids consumption. The thermodynamic model has been employed to characterize these fluids by describing saturated densities, vapor pressure, surface tension, temperature-enthalpy, and temperature-entropy diagrams, including further validation with binary mixtures. Then, based on technical criteria focused on the thermal efficiency and working and service fluids consumption, the soft-SAFT model has been used to conduct a feasibility study of HFEs as direct substitutes for HFC-245fa in such applications. Although pure fluids can not reach the same efficiency as the benchmark, HFE-356mmz, HFE-7000, and HFE-7100 appear as promising replacements, capable of approaching system requirements operating at low pressure with low cooling water and heating fluid flow rates, while exhibiting lower GWP values.