Radial inflow turbine is one of the crucial components of organic Rankine cycle (ORC) system, which has great impact on the performance of system. R245fa was selected as the working fluid to recycle the waste heat source with a temperature of 350 to 400 K. The genetic algorithm (GA) was employed in thermodynamic design to optimize the 10 key design parameters, which are needed in aerodynamic design of the ORC turbine. Isotropic efficiency was the fitness function of 10 key variables in GA. The three-dimensional geometry model was built based on the thermodynamic and aerodynamic design and then was imported into the commercial software ANSYS-CFX to conduct viscous numerical simulation. Based on the three-dimensional simulation, the off-design performance in different mass flow rate, static inlet temperature coupled with different rotational speed was investigated respectively. The results show that at design condition, the maximum efficiency deviation is only 2.5% with the rotational speed variations among the range of 10%, so the radial inflow turbine designed in this research possesses great off-design performance.