A high HDL cholesterol level has been mentioned as an anti-atherogenic factor in progressive cohort studies and in randomized clinical trials aimed at raising HDL levels. Moreover, acute infusion of synthetic HDL or its principal apolipoprotein, apoA-I, can induce the regression of atheromatous plaque in humans. Indeed, there has been a wealth of research demonstrating the beneficial processes in which HDL participates. HDL plays a key role in RCT and, importantly, facilitates the removal of cholesterol from intra-lesion macrophages [
25]. In addition, HDL has been shown to protect against LDL-induced monocyte migration into the sub-endothelial space in an endothelial cell/smooth muscle cell co-culture system [
26]. This is consistent with the finding that HDL can blunt expression of endothelial cell adhesion molecules [
27]. HDL can protect against oxidation of LDL or phospholipids [
28]. Other aspects of HDL function that are protective against atherosclerosis include promoting endothelial function by stimulating nitric oxide synthesis [
29] and preventing platelet aggregation and thrombin formation [
30]. There are multiple aspects of HDL function that are anti-atherogenic, and its role in RCT is one of them. Different subclasses of HDL play major roles as cholesterol acceptors in the extracellular region and plasma [
31]. Interestingly, a growing body of evidence has shown that fruitful cholesterol efflux is dependent both on high level of HDL cholesterol and on biological quality of different HDL particles [
17,
18]. The biological quality refers to the size, shape, and composition of HDL particles, which are notably various and dynamically inter-convertible [
32]. Evidently, each of the different pathways of cholesterol efflux prefers a specific subclass of the HDL particles as a cholesterol acceptor [
32]. Therefore, the presence of different HDL subspecies and dynamic conversion between these subspecies are determinants for RCT. Human and mouse studies have pointed out that preβ-HDL and mature HDL are the major cholesterol acceptors in plasma [
32]. Preβ-HDL is produced by interaction, and subsequent lipidation, of lipid-poor apoA-1 by ABCA1 or by HDL particle remodeling in the circulation [
19,
32]. One pathway for HDL particle remodeling involves plasma PLTP. PLTP fuses HDL particles generating larger HDL particles with concomitant production of small preβ-HDL [
33]. Given its role in HDL metabolism, PLTP’s role in reverse cholesterol transport deserves to be addressed.