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Inherently safer design is the new approach to maximize the overall safety of a process plant. This approach suggests some risk reduction strategies to be implemented in the early stages of design. In this paper a multi-objective optimization was performed considering economic, exergetic, and environmental aspects besides evaluation of the inherent safety level of a cascade refrigeration system. The capital costs, the processing costs, and the social cost due to CO2 emission were considered to be included in the economic objective function. Exergetic efficiency of the plant was considered as the second objective function. As a measure of inherent safety level, Quantitative Risk Assessment (QRA) was performed to calculate total risk level of the cascade as the third objective function. Two cases (ammonia and propane) were considered to be compared as the refrigerant of the high temperature circuit. The achieved optimum solutions from the multi objective optimization process were given as Pareto frontier. The ultimate optimal solution from available solutions on the Pareto optimal curve was selected using Decision Makings approaches. NSGA-II algorithm was used to obtain Pareto optimal frontiers. Also, three decision-making approaches (TOPSIS, LINMAP, and Shannon’s entropy methods) were utilized to select the final optimum point. Considering continuous material release from the major equipment in the plant, flash and jet fire scenarios were considered for the CO2/C3H8 cycle and toxic hazards were considered for the CO2/NH3 cycle. The results showed no significant differences between CO2/NH3 arid CO2/C3H8 with respect to economic and exergy efficiency objectives. But the CO2/NH3 cycle was the inherently safer cascade system in comparison with the CO2/C3H8 one. This is mainly due to the jet fire scenario for the CO2/C3H8 cycle in which the effects are very severe in the farther distance as well as the areas close to the release point. (C) 2016 Elsevier Ltd. All rights reserved.