Carotid atherosclerosis may lead to devastating clinical outcomes such as stroke. Data on the value of local factors in predicting progression in carotid atherosclerosis are limited. Our aim was to investigate the association of local endothelial shear stress (ESS) and low-density lipoprotein (LDL) accumulation with the natural history of atherosclerotic disease using a series of 3 time points of human magnetic resonance data. Three-dimensional lumen/wall reconstruction was performed in 12 carotids, and blood flow and LDL mass transport modeling were performed. Our results showed that an increase in plaque thickness and a decrease in lumen size were associated with low ESS and high LDL accumulation in the arterial wall. Low ESS (odds ratio [OR]: 2.99; 95% confidence interval [CI]: 2.31-3.88; P < .001 vs higher ESS) and high LDL concentration (OR: 3.26; 95% CI: 2.44-4.36; P < .001 vs higher LDL concentration) were significantly associated with substantial local plaque growth. Low ESS and high LDL accumulation both presented a diagnostic accuracy of 67% for predicting plaque growth regions. Modeling of blood flow and LDL mass transport show promise in predicting progression of carotid atherosclerosis.