• A mixture of R600a and R1150 was thermodynamically evaluated in auto-cascade cooling cycles. • The influence of the mass fraction, the discharge pressure and the phase-separator temperature were evaluated. • The results are especially sensitive to the temperature at the phase-separator and the mass fraction of the refrigerants. • The ejector as an expansion device can improve the COP by up to 12% with regard to the reference case. The temperatures required by ultra-low temperature applications, ranging from −50 °C to −100 °C, cannot be reached economically with single stage systems because of the limitation of the compression ratio. Different types of solutions such as cascade or two-stage systems could be implemented to achieve the desired working conditions. However, these systems are usually complex or too expensive. The solution might be found in the use of auto-cascade systems working with zeotropic mixtures. The present article proposes two modifications of the auto-cascade system by including an ejector device to improve the COP. The first modification includes the ejector as an expansion device at the outlet of the phase-separator, while the second includes the ejector as a pre-compression stage. A mixture of the hydrocarbons iso -butane (R600a) and ethylene (R1150) was used as an alternative to conventional refrigerants, which have a very high GWP. The study performed firstly assessed the sensitivity analysis of the free variables on the operating conditions of each cycle. The evaluated variables were the compressor pressure discharge, the mass fraction of the mixture and the phase separator temperature. In the case of the ejector enhanced cycles, the ejector efficiency and the motive pressure were additionally included. Then, the optimal operating conditions were found by means of an optimization process. The results showed a potential improvement in the COP of 12% for the case of the ejector as an expansion device, with an optimal mass fraction of 0.45 of ethylene. On the other hand, the ejector as a pre-compression stage did not show any improvement with regard to the reference case. The present study concludes that the mixture of ethylene and iso -butane is a suitable combination for auto-cascade cycles and that the ejector can be implemented to improve the COP without adding excessive complexity and cost.