Background: Atherosclerotic plaques may rupture without warning and cause acute cardiovascular syndromes such as heart attack and stroke. Methods to assess plaque vulnerability noninvasively and predict possible plaque rupture are urgently needed. Method: MRI-based three-dimensional unsteady models for human atherosclerotic plaques with multi-component plaque structure and fluid-structure interactions are introduced to perform mechanical analysis for human atherosclerotic plaques. Results: Stress variations on critical sites such as a thin cap in the plaque can be 300% higher than that at other normal sites. Large calcification block considerably changes stress/strain distributions. Stiffness variations of plaque components (50% reduction or 100% increase) may affect maximal stress values by 20–50 %. Plaque cap erosion causes almost no change on maximal stress level at the cap, but leads to 50% increase in maximal strain value. Conclusions: Effects caused by atherosclerotic plaque structure, cap thickness and erosion, material properties, and pulsating pressure conditions on stress/strain distributions in the plaque are quantified by extensive computational case studies and parameter evaluations. Computational mechanical analysis has good potential to improve accuracy of plaque vulnerability assessment.