Accurate prediction of the self-propulsion performance is one of the most important factors for energy-efficient design of a ship. In general, the hydrodynamic performance of a full-scale ship could be achieved by model-scale simulation or towing tank test with extrapolations. With the development of CFD methods and computing power, directly predict ship performance with full-scale CFD is an important approach. In this article, a numerical study on the full-scale self-propulsion performance with propeller operating behind ship at model- and full-scale is presented. The study includes numerical simulations using RANS method with double-model and VOF model respectively and scale effect analysis based on overall performance, local flow fields and detailed vortex identification. Verification study on grid convergence is also performed for full-scale simulation with global and local mesh refinements. And a series of sea trail tests were performed to collect reliable data for the validation of CFD predictions. The analysis of scale effect on hull-propeller interaction shows that the difference on hull boundary layer and flow separation is the main source of scale effect on ship wake. And the results of the fluctuations of propeller thrust and torque along with circulation distribution and local flow field show that propeller’s loading is significantly higher for model-scale ship. It is suggested that the difference on vortex evolution and interaction is more pronounced and have larger effects on ship’s powering performance at model-scale than full-scale according to the simulation results. From the study on self-propulsion prediction, it could be concluded that the simplification on free surface treatment does not only affect the wave-making resistance for bare hull but also the propeller performance and propeller induced ship resistance which can produced up to 5% uncertainty to the power prediction. Roughness is another important factor in full-scale simulation because it has up to approximately 7% effect on the delivery power. As a result of validation study, the numerical simulations of full-scale ship self-propulsion shows good agreement with the sea trail data especially for cases that have considered both roughness and free surface effects. This result will largely enhance our confidence to apply full-scale simulation in the prediction of ship’s self-propulsion performance in the future ship designs.