Purpose of Review <p>Atherosclerosis, an inflammatory disease of large arteries, is a major cause of cardiovascular disease and stroke. Its pathogenesis involves complex interactions among endothelial cells, smooth muscle cells, macrophages, and other immune cells, forming atherosclerotic plaques. Secreted protein acidic and rich in cysteine (SPARC), a protein widely present in various cell types, participates in numerous biological processes. This review aims to explore the pathophysiologic role of SPARC in atherosclerosis and its significance in diagnosis and treatment.</p> Recent Findings <p>Elevated expression of SPARC is observed in advanced atherosclerotic lesions and plasma concentrations of SPARC are higher in patients with ischemic cardiovascular disease. In a baboon model, SPARC expression correlates with LDL-C levels. However, the role and mechanism of SPARC in atherosclerosis remain to be explored.</p> Summary <p>In this review, we elaborate on the critical roles of SPARC in endothelial dysfunction, macrophage polarization, smooth muscle cell proliferation, migration, and phenotypic transformation during the atherosclerotic process. The effects of SPARC on immune cells are also mentioned. Finally, we analyzed the potential of SPARC in the diagnosis and treatment of atherosclerosis.</p>