Abstract Background Microembolism during cardiopulmonary bypass has been suggested as being the predominant cause of neurocognitive disorders after cardiac surgery. Shed blood, normally retransfused into the patient during cardiopulmonary bypass, is a major source of lipid microemboli in the brain capillaries. A newly developed technique based on acoustic standing-wave separation of particles in fluid in microchannels, with the capacity to remove lipid particles in blood, is presented. Methods A separator consisting of eight parallel, high-fidelity microfabricated channels was actuated with an ultrasound field to create a standing wave. Three different concentrations of lipid particles (diameter, 0.3 μm) were added to blood samples with increasing hematocrits and introduced into the separator channels to separate lipid particles and erythrocytes. Results The mean separation rates for lipid particles were 81.9% ± 7.6% and for erythrocytes 79.8% ± 9.9%, and both were related to the hematocrit level of the incoming blood sample. The procedure was atraumatic and did not cause hemolysis. Conclusions Particle separation by means of an acoustic standing-wave technique can be used for atraumatic and effective removal of lipid particles from blood, with the possible clinical implication of reducing neurocognitive complications after cardiopulmonary bypass.