• A comprehensive method to evaluate refrigerant alternatives is developed. • No mixture has higher COP, higher Q, lower GWP, and lower flammability than R134a. • Mixing R134a or R227ea with R152a creates a promising alternative to R134a. • The results of mixtures are compared to R134a and guide the design of alternatives. • The method can be extended for searching alternatives for other fluids. R134a will be phased out soon due to its high GWP. Replacing R134a with a low Global Warming Potential (GWP) and non– or slightly flammable fluids in the systems in stock should maintain the same level of system performance. This study focuses on the drop-in alternatives for R134a regarding a Mobile Air-Conditioning system. A simulation model coupled with a microchannel heat exchanger model is developed and validated for calculating the system Coefficient of Performance (COP) and capacity of the Mobile Air-Conditioning system. A comprehensive method is developed to evaluate the alternative candidates combining the performance simulation and the flammability estimated of mixtures. The evaluation includes the system performance, environmental impact, and flammability of alternative mixtures. 15 pairs of binary mixtures from six pure fluids (R134a, R1234yf, R1234ze(E), R32, R227ea, and R152a) with 99 compositions are evaluated as R134a drop-in replacements, and the results are discussed. There is no perfect mixture found that is nonflammable, has low GWP, and has higher system efficiency and capacity than R134a in this study. Using R152a as a drop-in replacement of R134a can increase the system efficiency and capacity, but R152a is flammable. By adding R134a or R227ea to R152a can reduce the flammability of the mixture. R152a/R134a, R152a/R1234yf, and R32/R152a have higher COP and capacity than R134a, but they are not safe or environmental friendly enough. The mixtures for replacing R134a as drop-in alternatives with low Global Warming Potential (less than 150 or 700), nonflammable or slightly flammable are listed and discussed. The method developed in this study can be extended to evaluate alternatives for replacing other working fluids in any thermal application that will be restricted.