Motivation: Atherosclerosis is a complex multi-pathway inflammatory disease where accumulation of oxidatively modified lipids and leukocytes in the arterial intima leads to plaque formation over time. Translating Apoe-/- mouse results to the clinical setting is complicated by uncertainty around (a) mechanisms underlying disease etiology, (b) relative importance of these mechanisms as drivers of progression, and (c) how these roles change in response to perturbation by therapeutic intervention or lifestyle changes. Results: We describe a large-scale mechanistic, mathematical model of atherosclerosis in the Apoe-/- mouse and its validation with in vivo Apoe -/- data. Major physiological components include cholesterol/macrophage trafficking, inflammation, endothelial function, oxidative stress, and thrombosis. Heterogeneity in disease progression, observed despite genetic uniformity and experimentally controlled conditions, was captured through “virtual mice”. This model may be used to optimize in vivo experiments and paves the way for a similar modeling approach for human disease. Availability: The model is available by remote desktop client at Apoe.entelos.com.