A thermodynamic model of Organic Rankine Cycle (ORC) system and an aerodynamic design model of a centrifugal turbine were conducted in this paper. Thermodynamic performance comparison of ORC using different working fluids (R123, R245fa, R600, R601a, R245ca, R141b) was achieved for a given amount of heat absorbed by the system. For a known heat source term whose thermophysical properties were specified, the aerodynamic and mechanical design of three centrifugal turbines having different stages have been undertaken, in which organic fluid like R123 was used as the working fluid. Three-dimensional modeling and optimization were subsequently applied to improve the design of the centrifugal turbine whose preliminary thermodynamic design was conducted based on one-dimensional theoretical model. The power and efficiency characteristics of the designed centrifugal turbines were then assessed by means of numerical simulations. Numerical results suggested that isentropic efficiency and output work of all the proposed centrifugal turbines operating at design conditions can exceed 82.7% and 330 kW, which satisfy the requirements of ORC system applications.