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Natural substances are becoming very promising for long term alternative for refrigeration purposes. In this paper, two natural refrigerants have been proposed and analyzed for a novel ejector expansion transcritical cascade refrigeration (NEETCR) system. Nitrous oxide (N 2 O) is used in the low temperature circuit (LTC) whereas carbon dioxide (CO 2 ) is used in the high temperature circuit (HTC) of the NEETCR system. The reject of refrigerant vapor heat in the HTC is carried out through the use of transcritical carbon dioxide Rankine cycle. This produces work, which will be used to reduce the consumption work of compressors and feed pump thereby resulting in the improvement of the energy efficiency of the whole system. The simulation results were obtained by a computer FORTRAN program, where REFPROP 9 database was used to get the refrigerant thermodynamic properties. The simulation results showed that the (NEETCR) system had higher coefficient of performance and higher system second law efficiency compared to the EETCR system. An enhancement more than 9% in the COP and exergy efficiency of NEETCR system was found in comparison with EETCR system, when the cooling capacity and operating conditions of the two systems were the same. The increase of COP of NEETCR system and its efficiency along with the reduction of power consumption make it more practical for the use in cooling applications. [ABSTRACT FROM AUTHOR]