The Organic Rankine Cycle (ORC) is a promising technology to convert low temperature heat to electrical power. It utilizes organic substances, which are often refrigerants, as working fluids. With the groups of hydrofluoroolefines (HFO) and hydrochlorofluoroolefines (HCFO), a new generation of refrigerants has been introduced within the last years. These refrigerants have a significantly smaller Global Warming Potential (GWP) compared to the currently dominating fluids, which are within the group of hydrofluorocarbons (HFC). A typical representative of HFC fluids for ORC applications is R245fa, with an GWP value of 1030. According to the thermophysical properties, promising low-GWP alternatives for this fluid are R1233zd(E) and R1224yd(Z) with a three orders of magnitude lower GWP value.The purpose of this paper is to investigate the applicability of these modern fluids as drop-in replacements for R245fa in existing ORC systems. For the evaluation of drop-in replacements, it has to be ensured, that on the one hand side, the materials within the system are compatible with the new fluid. On the other hand side, the operation condition and the performance of the system should be similar to the case with the HFC fluid. Therefore, a twofold approach is followed in this study: First, the material compatibility between the three fluids and typical elastomers is investigated. Second, all three fluids are tested in an ORC system under a wide range of operational conditions. With that approach, a general evaluation of the feasibility of a drop-in replacement can be made.As a conclusion, it can be stated, that both novel fluids R1233zd(E) and R1224yd(Z) are suitable for the drop-in replacement of R245fa in ORC systems. However, the results show, that the compatibility of R1233zd(E) with the investigated typical polymers is worse compared to R245fa and R1224yd(Z), pointing out the need for individual compatibility investigations when R1233zd(E) should be applied. Concerning system performance, the highest power output is still obtained with the high-GWP fluid R245fa. The maximum power output with R245fa is 326 W, which is 9% higher compared to R1233zd(E) and 12% higher compared to R1224yd(Z). In terms of thermal efficiency of the ORC system, R1233zd(E) leads to approximately 2% higher values compared to R245fa. In contrast to that, the thermal efficiency of R245fa and R1224yd(Z) is equal over a wide range of operation conditions.