We present a thermo-economic evaluation of binary power plants based on the Organic Rankine Cycle (ORC) for geothermal power generation. The focus of this study is to analyse if an efficiency increase by using zeotropic mixtures as working fluid overcompensates additional requirements regarding the major power plant components. The optimization approach is compared to systems with pure media. Based on process simulations, heat exchange equipment is designed and cost estimations are performed. For heat source temperatures between 100 and 180 °C selected zeotropic mixtures lead to an increase in second law efficiency of up to 20.6% compared to pure fluids. Especially for temperatures about 160 °C, mixtures like propane/isobutane, isobutane/isopentane, or R227ea/R245fa show lower electricity generation costs compared to the most efficient pure fluid. In case of a geothermal fluid temperature of 120 °C, R227ea and propane/isobutane are cost-efficient working fluids. The uncertainties regarding fluid properties of zeotropic mixtures, mainly affect the heat exchange surface. However, the influence on the determined economic parameter is marginal. In general, zeotropic mixtures are a promising approach to improve the economics of geothermal ORC systems. Additionally, the use of mixtures increases the spectrum of potential working fluids, which is important in context of present and future legal requirements considering fluorinated refrigerants.