Global warming is the leading environmental concern of the 21st century, promoting active areas of research as the development of low global warming potential (GWP) refrigerants such as hydrofluoroolefins (HFOs).This work investigates the performance of a 2 kW hermetic scroll expander by means of a semi-empirical model when replacing the original working fluid (R245fa) with low-GWP fluids. Calculation results of micro organic Rankine cycle (ORC) systems are presented, after setting the power output from the expander, and the relation between cycle efficiency and maximum cycle temperature is reported for seven selected fluids. In detail, almost equal performance of R1234ze(Z) compared to R245fa and slightly better performance when using R1224yd(Z) or R1233zd(E) are achieved, even though a modest increase of the fluid temperature at the expander inlet is necessary for the last two fluids. In case of lower heat sources, R1234yf, R1243zf and R1234ze(E) are indicated as working fluids and mixtures of HFOs are also considered to extend the operation range of the expander. On the other hand, limited to this case study, R1336mzz(Z) does not seem to be an interesting fluid, because of the calculated higher temperature at the expander inlet and lower expander efficiency.