The wider adoption of organic Rankine cycle (ORC) technology for power generation or cogeneration from renewable or recovered waste-heat in many applications can be facilitated by improved thermodynamic performance, but also reduced investment costs. In this context, it is suggested that the further development of ORC power systems should be guided by combined thermoeconomic assessments that can capture directly the trade-offs between performace and cost with the aim of proposing solutions with high resource-use efficiency and, importantly, improved economic viability. This paper couples, for the first time, the computer-aided molecular design (CAMD) of the ORC working-fluid based on the statistical associating fluid theory (SAFT)-gamma Mie equation of state with thermodynamic modelling and optimisation, in addition to heat-exchanger sizing models, component cost correlations and thermoeconomic assessments. The resulting CAMD-ORC framework presents a novel and powerful approach with extended capabilities that allows the thermodynamic optimisation of the ORC system and working fluid to be performed in a single step, thus removing subjective and pre-emptive screening criteria that exist in conventional approaches, while also extending to include cost considerations relating to the resulting optimal systems. Following validation, the proposed framework is used to identify optimal cycles and working fluids over a wide range of conditions characterised by three different heat-source cases with temperatures of 150 degrees C, 250 degrees C and 350 degrees C, corresponding to small- to medium-scale applications. In each case, the optimal combination of ORC system design and working fluid is identified, and the corresponding capital costs are evaluated. It is found that fluids with low specific-investment costs (SIC) are different to those that maximise the power output. The fluids with the lowest SIC are isoheptane, 2-pentene and 2-heptene, with SICs of 5620 pound, 2760 pound and 2070 pound per kW respectively, and corresponding power outputs of 32.9 kW, 136.6 kW and 213.9 kW. (C) 2018 The Authors. Published by Elsevier Ltd.