A computational fluid dynamics (CFD) model is presented to simulate the removal of lipid particles from blood using a novel ultrasonic quarter-wavelength separator. The Lagrangian-Eulerian CFD model accounts for conservation of mass and momentum, for the presence of lipid particles of a range of diameters, for the acoustic force as experienced by the particles in the blood, as well as for gravity and other particle-fluid interaction forces. In the separator, the liquid flows radially inward within a fluid chamber formed between a disc-shaped transducer and a disc-shaped reflector. Following separation of the lipid particles, blood exits the separator axially through a central opening on the disc-shaped reflector. Separator diameters studied varied between 12 and 18 cm, and gap sizes between the discs of 600 μm, 800 μm and 1 mm were considered. Results show a strong effect of residence time of the particles within the chamber on the separation performance. Different separator configurations were identified, which could give a lipid removal performance of 95% or higher when processing 62.5 cm3/min of blood. The developed model provides a design method for the selection of geometric and operating parameters for the ultrasonic separator.