Previously, the authors have shown that the molecular interaction between caveolin-1 and ATP-binding cassette transporter A1 (ABCA1) is associated with the high-density lipoprotein (HDL)-mediated cholesterol efflux pathway in aortic endothelial cells (ECs). This study analyzed the role ABCA1 plays in caveolin-1-mediated cholesterol efflux in aortic ECs. Knockdown of ABCA1 by siRNA in primary rat aortic ECs after cholesterol treatment did not affect caveolin-1 expression but led to the retention of caveolin-1 in the Golgi apparatus, impaired caveolin-1 oligomerization, and reduced cholesterol efflux. Immunoblotting assay and immunofluorescence microscopy demonstrated that HDL transiently up-regulated ABCA1 expression, induced caveolin-1 oligomerization, and promoted its Golgi exit, thereby enhancing cholesterol efflux. These HDL-induced events, however, were inhibited by down-regulation of ABCA1. It is concluded that HDL up-regulates ABCA1 expression, which in turn modulates the oligomerization and Golgi exit of caveolin-1 to enhance cholesterol efflux in aortic ECs.