Lymphatic vessels are essential for lipid absorption and transport. Despite increasing numbers of observations linking lymphatic vessels and lipids , little research has been devoted to address how dysregulation of lipid balance in the blood , ie , dyslipidemia , may affect the functional biology of lymphatic vessels. Here , we show that hypercholesterolemia occurring in apolipoprotein E-deficient (apoE ؊/؊ ) mice is associated with tissue swelling , lymphatic leakiness , and decreased lymphatic transport of fluid and dendritic cells from tissue. Lymphatic dysfunction results in part from profound structural abnormalities in the lymphatic vasculature: namely , initial lymphatic vessels were greatly enlarged , and collecting vessels developed notably decreased smooth muscle cell coverage and changes in the distribution of lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1). Our results provide evidence that hypercholesterolemia in adult apoE ؊/؊ mice is associated with a degeneration of lymphatic vessels that leads to decreased lymphatic drainage and provides an explanation for why dendritic cell migration and , thus , immune priming , are compromised in hypercholesterolemic mice.