The Montreal Protocol has a stringent timeline for the phase-out of HCFC refrigerants, including R-22, in both developing and developed nations. However, in most developing nations, high ambient temperatures limit the use of alternative refrigerants due to performance and safety concerns. Furthermore, the developed world’s transition through higher global warming potential (GWP) refrigerants like HFC and HFC blends resulted in significant direct CO2 equivalent emissions. It is imperative to develop a bridge for developing nations to avoid the transition from HCFC to HFC and then from HFC to alternative lower GWP refrigerants. In this paper, we summarize an experimental campaign on alternative refrigerant evaluation for an R-22 mini-split system. The experimental evaluation was performed according to ANSI/ASHRAE Standard 37 and the performance was rated according to ANSI/AHRI 210-240 standard. Furthermore, extended test conditions were evaluated at outdoor ambient temperatures of 46°C, 52°C, and 55°C. R-22 alternative refrigerants included propriety refrigerant blends (ARM-20b, DR-3, and N-20b). The unit performance was first verified using the baseline refrigerant and then drop-in refrigerant evaluation followed including soft optimization to ensure refrigerant performance is adequately represented. The soft optimization included: 1) charge optimization, 2) lubricant, and 3) flow control. The paper presents the relative performance (efficiency and capacity) of the alternative refrigerants compared to the baseline refrigerant at the different operating conditions. We conclude with remarks about the alternative refrigerants for R-22 applications in high ambient temperature regions.