BACKGROUND: The composition of an atherosclerotic plaque is considered more important than the degree of stenosis. An unstable lesion may rupture and cause an acute thrombotic reaction. Most of these lesions contain a large lipid pool covered by an inflamed thin fibrous cap. The stress in the cap increases with decreasing cap thickness and increasing macrophage infiltration. Intravascular ultrasound (IVUS) palpography might be an ideal technique to assess the mechanical properties of high-risk plaques. TECHNIQUE: Palpography assesses the local mechanical properties of tissue using its deformation caused by the intraluminal pressure. IN VITRO VALIDATION: The technique was validated in vitro using diseased human coronary and femoral arteries. Especially between fibrous and fatty tissue, a highly significant difference in strain (p = 0.0012) was found. Additionally, the predictive value to identify the vulnerable plaque was investigated. A high-strain region at the lumen-vessel wall boundary has an 88% sensitivity and 89% specificity for identifying such plaques. IN VIVO VALIDATION: In vivo, the technique was validated in an atherosclerotic Yucatan minipig animal model. This study also revealed higher strain values in fatty than fibrous plaques (p