. Atherosclerosis is the buildup of fats, cholesterol, and other substances on the inner walls of arteries. It can affect arteries of heart, brain, arms, legs, pelvis and kidney, resulting in ischemic heart disease, carotid artery disease, peripheral artery disease and chronic kidney disease. Laser-based treatment techniques like laser atherectomy can be used to treat many common atherosclerostic diseases. However, the use of laser-based treatment remains limited due to the high risk of complications and low efficiency in removing atherosclerostic plaques as compared with other treatment methods. In this study, we developed a technology that used high intensity focused ultrasound to assist laser treatment in the removal of the lipid core of atherosclerotic plaques.. The fundamental mechanism to disrupt atherosclerostic plaque was to enhance the mechanical effect of cavitation during laser/ultrasound therapy. To promote cavitation, spatiotemporally synchronized ultrasound bursts of 2% duty cycle at 0.5 MHz and nanosecond laser pulses at 532 nm wavelength were used. Experiments were first performed on pig belly fat samples to titrate ultrasound and laser parameters. Then, experiments were conducted on human plaque samples, where the lipid depositions of the plaques were targeted.. Our results showed that fat tissue could be removed with an ultrasound peak negative pressure (PNP) of 2.45 MPa and a laser radiant exposure as low as 3.2 mJ mm. The lipid depositions on the atherosclerostic plaques were removed with laser radiant exposure of 16 mJ mmin synchronizing with an ultrasound PNP of 5.4 MPa. During all the experiments, laser-only and ultrasound-only control treatments at the same energy levels were not effective in removing the lipid.. The results demonstrated that the addition of ultrasound could effectively reduce the needed laser power for atherosclerotic plaque removal, which will potentially improve treatment safety and efficiency of current laser therapies.