The performance of Organic Rankine Cycle (ORC) is significantly influenced by the used working fluid and the operating condition. Consequently, this paper presents a systematic model for the efficient design of working fluids and the optimization of cycle parameters at the molecular scale, so that optimal working fluids can be identified by simultaneously considering cycle parameters, environmental and safety properties. In the proposed model, working fluids are generated via the combination of groups. The required properties, which consist of thermodynamic, environmental and safety properties, are estimated by the published group contribution methods. Based on these estimated properties, cycle optimizations are performed to obtain the optimal performance of working fluids using an ORC model. Thereafter, optimal working fluids are identified, according to the cycle parameters, environmental and safety properties. Furthermore, working fluids design and cycle optimization for an example are conducted to demonstrate the proposed model. The optimal candidates, namely R254eb, R254cb, are found for the considered example through proposed methodology. The novel working fluids, which are firstly reported in ORC applications, are worth being studied in-depth through time-consuming and expensive experiments. (C) 2017 Elsevier Ltd. All rights reserved.