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UASB reactors are a promising option for environmentally friendly wastewater treatment due to their reduced carbon footprint and their capacity to treat a variety of wastewater strengths, among other recognized advantages over alternative wastewater treatment systems. The Influent Distribution System (IDS) is a critical structure for generating granules in a UASB reactor since it provides the required flow hydrodynamics for their formation. Thus, the objective of this study was to evaluate and compare the efficiency of five IDS configurations to generate ideal granulation conditions using Computational Fluid Dynamics (CFD) simulations. The IDS configurations were as follows: (C1) single radial inflow, (C2) upward axial inflow, (C3) downward distributed axial inflow, and two novel configurations in the form of (C4) double opposite radial inflow and (C5) downward tangential inflow. The hydrodynamic response of configuration C1 was validated in a physical model with dynamic Froude similitude. The granulation measurement was velocity-based in the reactor reaction zone using steady-state CFD simulations. The novel IDS configuration C4 was the one that resulted in the highest granulation volume, with up to 45.5% of the potential granulation volume of the UASB reactor, in contrast to the IDS C2 that obtained the lowest granulation with only 10.8%. Results confirm that the IDS directly impacts the hydrodynamics of the reactor and that model-based design can be used to ascertain IDS configurations that better promote granulation in UASB reactors. Full article