The Dense Discrete Phase Model coupled with an agglomeration model is developed and validated for the simulation of industrial cyclones with high solid loads. The performance of the model is influenced by sub-models, model parameters, and numerical parameters. To optimize the performance of the present CFD model, an extensive sensitivity analysis was performed, varying one sub-model or parameter at a time, and systematically assessing the effect on the results through comparisons with measured pressure drop and separation efficiency of a highly loaded pilot-scale cyclone. The investigation shows that the turbulence model and particle-particle restitution coefficient have the strongest influence. This study concludes with the recommendation of a set of sub-models, model parameters, and numerical parameters providing the best prediction of the hydrodynamics of large-scale highly loaded cyclones. In addition, the impact of some operating conditions on the performance of a large-scale highly loaded cyclone were examined. • Simulation of highly loaded cyclones: effects of sub-models and model parameters. • Particle-particle restitution coefficient and turbulence model influence the most. • The impact of particle-particle interaction force modeling is minor. • Most suitable sub-models, model parameters, and numerical parameters are suggested. • The impact of operating conditions on the performance of the cyclone was examined.