High levels of emissions of ozone-depleting substances and. greenhouse gases from supermarkets around the world can be attributed to the leakage of hydrofluorocarbons (HFCs) and the generation of electric power required for retail food refrigeration. Indirect refrigeration loops are ideally suited for reductions mandated by regulation standards because they reduce leakage and can lead to significantly lower total energy consumption. Hence, the design and identification of fluids that boost refrigeration performance while meeting safety and environmental guidelines is of considerable interest. Using a recently developed molecular design methodology (Samudra and Sahinidis, AIChE J., published online Apr 25, 2013, 10.1002/aic.14112) as our starting point, in this work, we developed a model and search technique for identifying ideal secondary refrigerants. Accurate property models that predict characteristic refrigerant properties guided the search for molecules. We also included environmental and safety metrics [biodegradability and lethal concentration. (LC50)], along with performance criteria for heat transfer efficiency, to analyze the candidate molecules. We identified a number of novel molecules as well as known compounds that have not been used as secondary refrigerants.