Abstract Single and multi-stage Joule-Thompson refrigerators operating with natural nitrogen-hydrocarbon mixtures are marketable for creating refrigeration equipment for freezing and cryopreservation of biomedical materials, liquefaction of certain gases, high-temperature superconductors cooling, conducting climate tests without using cryogenic liquids. One of the main objectives of the development of such refrigerators is to determine the optimal weight of mixed-refrigerant charge with the known geometry of the refrigeration circuit and to ensure the optimal “circulating” composition in the steady-state mode. This article proposes an analytical method for solving this problem and presents the experimental results. The accuracy of the method is determined by the validity of calculating thermodynamic properties of the mixed refrigerants forming solutions with limited solubility in the liquid phase and by taking into account the shift of the “circulating” working body composition relative to the “charge” composition in the steady-state mode due to structural specifics of real refrigerators. The application of the method will allow reducing the time and cost of experimental development of new refrigeration equipment.