This article presents simulated and experimental performance evaluations of a few selected low global warming potential refrigerants as alternatives to HCFC-22 for room air conditioners. The alternatives considered are HC-290, HC-1270, HFC-161, HFC-32, and HFC-1234yf. The performance of each alternative has been evaluated by optimizing heat exchangers, compressors, and capillary for the maximum EERAC. Experiments were also conducted as per IS 1391 Part 1 for a few alternatives, including HC-290, HFC-161, and HFC-32. HC-290 and HFC-32 gave an EERAC of 3.7. The experiments indicate that HC-290 offers the best performance, and room air conditioners that have a capacity of less than 5.2 kW can meet the exiting safety standards. The discharge temperatures of HFC-32 are relatively high and need special attention in the compressor design. HFC-161 is also a potential ultra-low global warming potential alternative to HCFC-22, once its safety classification is established.