Due to significant energy/exergy losses in expansion part of the cascade vapor compression cooling (C-VCC) systems in process engineering, the use of ejector expanders has been widely recommended. Although such an idea improves the energy and exergy performance indicators along with the unit cost of the process, safety aspect of the plant degrades considerably. In order to quantitatively investigate the role of ejector expander in safety of the C-VCC systems, quantitative risk assessment (QRA) along with 4E (energy, exergy, economic, and environment) analysis of the basic C-VCC (BC-VCC) system and ejector expander C-VCC (EEC-VCC) system are carried out and the results are compared with each other around the optimal and base points. In the base mode, the contribution of the expansion process to the overall risk of the BC-VCC system increases from 4.33 $/year to 50.56 $/year (for NH3) and from 116 $/year to 1393 $/year (for Propane) due to the employment of ejector expander instead of the expansion valve. Also, that means using NH3 instead of Propane in the EEC-VCC system substantially improves safety aspect of the whole unit. Although the maximum number of death is obtained due to release of Propane from the condenser of the system during the Flash Fire accident, the compressor of the hightemperature circuit (HTC) highly contributes to the overall risk due to its high release frequency. The results of multi-objective optimization for the NH3/CO2-based BC-VCC system showed that the COP (coefficient of performance), exergy efficiency, total cost, and risk can be improved by 56.66 %, 24.6 %, 26.14 %, and 1.78 %, respectively. Considering Propane/CO2 as a refrigerant pair used in the BC-VCC system, the COP, exergy efficiency, total cost, and risk were improved by 59.47 %, 26.77 %, 19.94 %, and 16.22 %, respectively. As an important conclusion, although employing ejector expander in the NH3/CO(2 )or Propane/CO2 BC-VCC system improves thermodynamic and cost metrics, such consideration significantly degrades the risk of the plant. (C) 2020 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.