Several media report highlight on that the pharmaceutical companies require ultra-low temperatures −80˚C to transport and store its COVID-19 vaccines. This research presents the thermodynamic analysis on cascade refrigeration system (CRS) with several refrigerant pairs which are R32/R170, R123/R170, R134a/R170, R404A/R170, R407c/R170, R410/R170, and the hydrocarbon (HC) refrigerant pair Propane/Ethane, namely R290/R170. Besides, the results of R22/R170 pair, which is not recommended to be used due to phase out of R22 as per Montréal Protocol, are included as base case to compare the novel hydrocarbon pairs in CRS and the old trend of refrigerant pairs. Thermodynamic properties of all these pairs were investigated and compared under different intermediate temperature used in CRS heat exchanger, which thermally connected both the Low and High temperature cycles (LTC) and (HTC). By applying the first law of thermodynamics, the coefficients of performance (COPs) and the specific power consumptions (SPC) in kW/TR are presented and compared. In addition, by applying the second law of thermodynamics the exergetic efficiencies were estimated. The results reveal the promising opportunity of using the HC pair (R290/R170). The minimum SPC in kW/TR is recorded for the pair R123/R170. One the other hand, the highest exegetic efficiency values are observed to be 40%, 38%, and 35% for the pairs R123/R170, R290/R170, and R134/R170, respectively. This research concludes that the HC pair (R290/R170) is highly recommended for CRS applications either to transport the COVID-19 or store it in cold storage rooms in hospitals and clinics. All precautionary measures should be carefully applied in design and operation of HC pair (R290/R170) due to its flammability hazard.