Cardiovascular disease (CVD) is the deadliest disease in the US and finding cures for CVD has been a pressing and challenging problem in biomedical science. Atherosclerosis is a pathological condition caused by an elevated plasma LDL cholesterol level and its deposition in the arterial wall. Although cholesterol-lowering therapies are currently effective in reducing circulating LDL cholesterol level, clinical trials have shown limited impact on reducing CVD risk. Thus, a supplemental treatment is urgently needed. Subendothelial LDL retention in the arterial wall is an early step in the atherogenic process, and finding the regulators that can be targeted to block this retention offers an alternative approach for early prevention. This review first presents the current understanding about the mechanism of the atherosclerosis development, and then focus on perlecan and its role in atherosclerosis. Perlecan is a major arterial proteoglycan consisting of a core protein and three heparan sulfate (HS) side chains. Many studies have linked perlecan to atherosclerosis because its HS side chains interact with LDL. Recently, we reported that the perlecan core protein also interacts with LDL via its LDL receptor (LDLR)-like domain II. Critical to the interaction is the sialic acid modification on the domain. In this review, the recent findings and the potential role of the arterial sialic acid in the early subendothelial LDL retention are discussed.