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This experimental study evaluates the energy performance and climatic changes of a cascade cooling system operating with the R134a/R744 pairs (cooling capacity of 4.5-6 kW) and R438A/R744. In both cases, the low-temperature refrigerant, R744, operated under subcritical conditions. The experimental apparatus basically consists of two vapor-compression cycles coupled by a plate cascade condenser. Two operational variables, from R744 cycle, were controlled: the degree-of-superheat and the compressor frequency. The experiment was initially assembled to pair R134a/R744. Subsequently, the R134a refrigerant charge in the high-temperature cycle was replaced by R438A, on a drop-in basis. The two systems, R134a/R744 and R438A/R744, were compared for similar cooling capacities and cold chamber air temperatures. Results showed that the energy consumption of the high-temperature compressor, operating with R438A, was higher than R134a for all tests. As a result, the COP values for R438A/R744 were 30% lower than those for R134a/R744. The greenhouse gases emissions of the two systems were evaluated using the total equivalent warming impact factor, TEWI, whose value for the R438A/R744 pair was approximately 29.5% higher, compared with R134a/R744. Since R438A was originally designed to substitute R22, a few comparative tests were carried out with the latter, always with R744 as the low-temperature cycle working fluid.