This paper quantifies and compares the cooling performance and refrigerant and fuel cost savings to automobile manufacturers and owners of secondary-loop mobile air conditioners (SL-MACs) using refrigerants hydrofluorocarbon (HFC)-134a and the available alternatives HFC-152a and HFO-1234yf. HFC-152a and HFO-1234yf are approved for use by the United States Environmental Protection Agency (US EPA) and satisfy the requirements of the European Union (EU) F-Gas Regulations. HFC-152a is inherently more energy efficient than HFC-134a and HFO-1234yf and in SL-MAC systems can generate cooling during deceleration, prolong comfort during idle stop (stop/start), and allow powered cooling at times when the engine can supply additional power with the lowest incremental fuel use. SL-MAC systems can also reduce the refrigerant charge, emissions, and service costs of HFO-1234yf. The paper is informed by previous studies of secondary loop systems and an ongoing demonstration of SL-MACs designed for India where there are long hot and humid cooling seasons, relatively expensive fuel, and highly congested driving as well as uncrowded open-road driving. That demonstration determines a baseline for the cooling performance and energy efficiency of HFC-134a and tests the same parameters for HFO-1234yf and HFC-152a. The paper includes a detailed analysis of the life cycle environmental impacts of secondary loop versus direct expansion systems and a comparison of the eligible refrigerants, as well as a description of some of the most important international regulations affecting mobile air conditioning refrigerant choices.