Our findings indicate that accrual of galectin-3–negative macrophages is associated with atherosclerosis progression in 2 diverse animal models of atherosclerosis and relate to an unstable plaque phenotype in humans; suggesting absence of galectin-3 delineates a macrophage subset that is associated with atherosclerotic plaque progression and instability. This evidence concerns the gene LGALS3 and atherosclerosis.