Waste heat recovery by a thermodynamic organic Rankine cycle (ORC) is an auspicious technique to increase the efficiency of motor vehicles and therefore reduce fuel consumption and carbon dioxide emission. Instead of reliance on a limited number of currently known ORC fluids, a high-throughput screening (HTS) was performed in the search for the optimal fluid. This screening covered almost the complete known chemical space based on the structures provided by the PubChem database with more than 72 million entries. After application of structural and thermodynamic filter criteria based on quantum chemical calculations for more than 2 million structures, a set of 3174 potential working fluids was considered for a ranking by thermodynamic performance. A combination of computational chemistry methods to predict all physicochemical properties of interest by the COSMOtherm software (e.g., vapor pressures, critical points) and thermodynamic process simulation (e.g., net power output) by the fast simulation tool DetailSimORC was applied. The COSMO-RS theory was combined with a generalized Patel-Teja equation of state to extend the applicability range of the thermodynamic calculations up to the critical point. The screening turned out to be successful and revealed that only 12 compounds in the top 100 list (ranked by thermodynamic performance) have been considered before as ORC working fluids.