Abstract In the European Union F-gas Regulation limited the use of some refrigerants in several applications. Regarding the domestic refrigeration sector, the F-gas Regulation banned the use of refrigerants with GWP values higher than 150. This fact led the scientific community to search for a replacement of R-134a, that is the most common refrigerant used in domestic refrigerators in USA. In this work, a comprehensive environmental analysis of the drop-in substitution of R-134 with a low GWP refrigerant (R-152a) in a no-frost domestic refrigerator was performed. The comparison, based on experimental data, between the environmental performance of the refrigeration system with the two refrigerants was carried out developing two different evaluation methods, which led to the evaluation of TEWI and LCCP, respectively. Both these metrics consider both direct and indirect contributions to global warming. Historical data of different countries were used to forecast the carbon intensity values for the next 15 years, which were then used to evaluate indirect emissions of the system during its lifetime. Considering the Italian case study, the results showed that the refrigerator working with an optimal charge of R-152a, identified as the mass charge that minimises TEWI and/or LCCP index, has better environmental performance than the system working with R-134a, with a reduction of TEWI and LCCP values of 10.3% and 9.4%, respectively. The same comparison, in terms of LCCP, was also performed for other European countries, showing a strong dependence of the LCCP index on carbon intensity values.