By employing the SAFT-VR Mie equation of state, molecular-based models are developed from which the thermodynamic properties of pure (i.e., single-component) organic fluids and their mixtures are calculated. This approach can enable the selection of optimal working fluids in organic Rankine cycle (ORC) applications, even in cases for which experimental data relating to mixture properties are not available. After developing models for perfluoroalkane (n-C4F10 + n-C10F22) mixtures, and validating these against available experimental data, SAFT-VR Mie is shown to predict accurately both the single-phase and saturation properties of these fluids. In particular, second-derivative properties (e.g., specific heat capacities), which are less reliably calculated by cubic equations of state (EoS), are accurately described using SAFT-VR Mie, thereby enabling an accurate prediction of important working-fluid properties such as the specific entropy. The property data are then used in thermodynamic cycle analyses for the evaluation of ORC performance and cost. The approach is applied to a specific case study in which a sub-critical, non-regenerative ORC system recovers and converts waste heat from a refinery flue-gas stream with fixed, predefined conditions. Results are compared with those obtained when employing analogue alkane mixtures (n-C4H10 + n-Ci(10)H(22)) for which sufficient thermodynamic property data exist. When unlimited quantities of cooling water are utilized, pure perfluorobutane (and pure butane) cycles exhibit higher power outputs and higher thermal efficiencies compared to mixtures with perfluorodecane (or decane), respectively. The effect of the composition of a working-fluid mixture in the aforementioned performance indicators is non-trivial. Only at low evaporator pressures (<10 bar) do the investigated mixtures perform better than the pure fluids. A basic cost analysis reveals that systems with pure perfluorobutane (and butane) fluids are associated with relatively high total costs, but are nevertheless more cost effective per unit power output than the fluid mixtures (due to the higher generated power). When the quantity of cooling water is constrained by the application, overall performance deteriorates, and mixtures emerge as the optimal working fluids. (C) 2015 The Authors. Published by Elsevier Ltd.