In order to discuss the feasibility of using R744/R744 cascade refrigeration system (CRS) instead of R744/R717 CRS, six configurations of R744/R744 CRS assisted with expander and mechanical subcooling system (MS) are analyzed. Based on the thermodynamic analysis, the results show that the high pressure, the condensing temperature of the low-temperature cycle (LTC), and the degree of subcooling of LTC and the high-temperature cycle (HTC) are three important operating parameters with an optimum value corresponding to the maximum coefficient of performance (COP). Compared with other CRSs, CRS with HTC throttling valve and MS of HTC (CTSH) and CRS with HTC expander and MS of HTC (CESH) show an excellent performance. CESH has the highest COP and is improved by an average of 13.8% compared with the COP of R744/R717 CRS. The COP of CTSH is improved by an average of 4.2% compared with the COP of R744/R717 CRS. In conclusion, it is an efficient way to improve performance that CRS combines MS in HTC and HTC expander. And it is possible R744/R744 CRS instead of R744/R717 CRS.