The acute phase protein Haptoglobin (Hpt) binds ApoA-I and impairs its stimulation of Lecithin-Cholesterol Acyl-Transferase (LCAT), an enzyme playing a key role in an anti-atherosclerotic process called reverse cholesterol transport (RCT). LCAT converts cholesterol (C) into cholesteryl esters (CE) for HDL-mediated transport. Beyond the key role in RCT, the anti-inflammatory activity of ApoA-I is largely recognized. We previously reported that an ApoA-I mimetic peptide, P2a displaces Hpt from ApoA-I and restores the LCAT activity in vitro. Our aim was to study if P2a displaces Hpt from ApoA-I in vivo in inflamed mice and if this event is linked to an anti-inflammatory activity. Inflammation was induced by carrageenan injection. Cholesterol esterification significantly decreased in inflamed mice during oedema development and negatively correlated with Hpt/ApoA-I ratio. The administration of the peptide P2a significantly restored the C esterification. Also, P2a displays an anti-inflammatory effect on the late phase of oedema with a reduction in COX-2 expression coupled to an inhibition of PGE2, implying that, in presence of P2a, CE/C ratio rescue and oedema inhibition are related. We conclude that P2a, by virtue of its ability to bind Hpt, makes ApoA-I available to stimulate LCAT and to play its anti-inflammatory role. These data suggest that peptides able to displace Hpt might be useful in the treatment of inflammatory cardiovascular diseases such as atherosclerosis.