Deterministic lateral displacement (DLD) is a high-resolution passive microfluidic separation method for separating micron-scale particles according to their size. Optimizing these microsystems for larger throughputs and particle concentrations is of interest for industrial applications. This study evaluates the limitations of the functionality of the DLD separation principle under these specific conditions. For this reason, different particle volume fractions (up to 11%) and volumetric flow rates (corresponding to Reynolds numbers up to 50) were varied within the DLD microsystem and tested in different combinations. Resolved two-way coupled computational fluid dynamics/discrete element method (CFD-DEM) simulations including spherical particles were performed. The results show a general increase in the critical diameter with increasing volume fraction and decreasing separation efficiency. The largest tested Reynolds number (Re = 50) results in the highest separation efficiency, particularly at low volume fractions, and is only slightly less efficient than low Reynolds numbers as the volume fraction increases. The results indicate that by limiting the volume fraction to a maximum of 3.6%, the flow rate and the associated separation rate can be increased while maintaining a high separation efficiency.