Recombinant-ApoA-I(M) (rApoA-I(M)) administration has been shown to regress and stabilize atherosclerotic plaques. However, the mechanisms responsible for these beneficial effects are not fully understood. The aims of the present study were to define whether the benefits of rApoA-I(M) treatment were mediated via an enhanced reverse cholesterol transport (RCT) and/or anti-inflammation-related mechanisms. Advanced aortic lesions were induced in New Zealand White rabbits (n= 16). Animals were randomized to placebo or rApoA-I(M) (rApoA-I(M)/phospholipids; ETC-216), two infusions 4 days apart. Four days after last dose, aortas and livers were processed for cholesterol content, expression of RCT-related receptors (ATP-binding cassette A-1 [ABCA-1] and scavenger receptor BI [SR-BI]), and inflammation-related markers (inducible nitric oxide synthase [iNOS] and capase-3). Oxidative stress was assessed in the vessel wall and in plasma. rApoA-I(M) administration resulted in a significant reduction in the hepatic and aortic cholesterol content without differences in plasma levels. This effect was associated with an up-regulation of vessel wall ABCA-1, as well as a hepatic and arterial-wall SR-BI up-regulation. Systemic and atherosclerotic-plaque inflammation markers were significantly reduced by the rApoA-I(M) administration, as demonstrated by a reduction in circulating oxidative stress markers and prostaglandin F1-alpha levels, and the down-regulation of the iNOS and caspase 3 in the aortic lesions. rApoA-IM up-regulated the ABCA-1 and SR-BI levels to a greater extent than the wild-type form of apoA-I in in vitro studies done with lipid-rich macrophages. Our data suggest that rApoA-I(M) administration enhances RCT and induces a 'rescue' from the global inflammatory status associated with atherosclerotic disease. The Milano form of apoA-I seems to be more efficient in RCT than the apoA-I wild-type.