Hydrofluoroolefin-based refrigerant (2,3,3,3-tetrafluoropropene, namely, HFO-1234yf), which has been developed as an environmentally friendly refrigerant, is proposed as a direct replacement solution in automotive air-conditioning compressor applications. In the present work, the wear mechanisms of this refrigerant using gray cast iron interfaces were investigated under a wide range of operating conditions. A critical velocity was measured from scuffing type experiments, where beyond that maximum interfacial loads did not change significantly with sliding velocity, suggesting a mechanical rubbing-type wear mechanism. Below the critical velocity, scuffing loads decreased almost linearly with sliding velocities. Wear type experiments identified two different wear mechanisms, namely, oxygen-dominating and fluorine-dominating wear, depending on sliding velocities and normal loads. Oxygen-dominating wear mechanism prevailed under low sliding velocities and normal loads. In contrast, fluorine-dominating wear was predominant under moderate sliding velocities and low or moderate loads. The formation of protective tribofilms and their effect on the wear mechanism was used to construct a wear map.