The reverse cholesterol transport mediated by high-density lipoprotein (HDL) is an important mechanism for maintaining body cholesterol at normal levels and, hence, the critical anti-atherogenic action of the lipoprotein. Recent studies, however, showed that HDL exerts a variety of anti-inflammatory and anti-atherogenic actions independently of the cholesterol metabolism. On the other hand, statins, inhibitors of HMG-CoA reductase, were initially developed to lower low-density lipoprotein cholesterol in plasma, and they are now recognized to exert a variety of pleiotropic or beneficial actions. Thus, although the mechanisms are different, both endogenous HDL and exogenous statins regulate cholesterol balance in a negative manner and exert a variety of beneficial actions independently of their cholesterol-lowering activity. These results raise the possibility that statins act in part through modulating the plasma levels of HDL and/or its actions. Here, we reviewed the cross-talk mechanism between statins and HDL in anti-inflammatory and anti-atherogenic actions, with a focus on scavenger receptor class B type I, one of main players involved in the cholesterol metabolismindependent HDL actions, and its downstream signaling pathway, leading to the activation of endothelial nitric oxide synthase and the inhibition of adhesion molecule expression in endothelial cells.