An efficient mobile air conditioning (MAC) system using a safe and climate-friendly refrigerant is necessary for human comfort, increasing the vehicle’s energy performance, and reducing the fuel/electricity consumption. In the current work, we perform a drop-in experimental comparison for low GWP alternatives to R134a in reversible MAC systems. The study compares two lower global warming potential (GWP) refrigerants; R456A, a non-flammable refrigerant for R134a direct MAC replacement, and R1234yf, an ultra-low GWP and mildly flammable refrigerant that is the standard for new MAC systems. The system’s operational and energy performance is investigated, simulating a wide range of indoor and outdoor steady-state conditions. The measurements are recorded operating a fully monitored vapour compression test rig that uses secondary circuits to set the target conditions. In the heating mode (heat pump), the evaporation temperatures are set at −10 °C, −5 °C, and 0 °C, and condensation temperatures at 40 °C, 50 °C, and 60 °C. In cooling mode (air conditioning), the condensation temperatures are 37.5 °C, 45 °C, and 52.5 °C and are combined with evaporation temperatures of −7.5 °C, 0 °C, and 7.5 °C. In the heating mode, R456A presented a competitive COP to R134a with a reduction of less than 5 %, more remarkable at lower evaporation temperatures. In the cooling mode, R456A showed the lowest COP at a low condensation temperature. R456A and R1234yf COP are comparable at a higher condensation temperature, which suits the T3 climate conditions.