Objective - To determine the properties of a peptide synthesized from D-amino acids corresponding to residues 113 to 122 in apolipoprotein (apo) J. Methods and Results - In contrast to D-4F, D- [113-122]apoJ showed minimal self-association and helicity in the absence of lipids. D-4F increased the concentration of apoA-I with pre-β mobility in apoE-null mice whereas D- [113-122]apoJ did not. After an oral dose D- [113-122]apoJ more slowly associated with lipoproteins and was cleared from plasma much more slowly than D-4F. D- [113-122]apoJ significantly improved the ability of plasma to promote cholesterol efflux and improved high-density lipoprotein (HDL) inflammatory properties for up to 48 hours after a single oral dose in apoE-null mice, whereas scrambled D- [113-122]apoJ did not. Oral administration of 125 μg/mouse/d of D- [113-122]apoJ reduced atherosclerosis in apoE-null mice (70.2% reduction in aortic root sinus lesion area, P=4.3×10-13; 70.5% reduction by en face analysis, P=1.5×10-6). In monkeys, oral D- [113-122]apoJ rapidly reduced lipoprotein lipid hydroperoxides (LOOH) and improved HDL inflammatory properties. Adding 250 ng/mL of D-[113-122]apoJ (but not scrambled D- [113-122]apoJ) to plasma in vitro reduced LOOH and increased paraoxonase activity. Conclusions - Oral D- [113-122]apoJ significantly improves HDL inflammatory properties in mice and monkeys and inhibits lesion formation in apoE-null mice. © 2005 American Heart Association, Inc.