Raising high-density lipoprotein (HDL) levels is proposed as an attractive target to treat cardiovascular disease. However, a number of clinical studies examining the effect of HDL-raising therapies have been prematurely halted due to futility. Therefore there is a need for alternative therapies. Infusion of reconstituted HDL (rHDL) particles is still considered as a viable approach to increasing HDL levels. In this study we have profiled the anti-inflammatory effects of a trimeric-HDL particle. We show that trimeric apoA-I and rHDL particles promote cholesterol efflux to a similar rate as native apoA-I particles in both ABCA1-dependent and -independent pathways. Trimeric particles inhibited ICAM-1 and VCAM-1 expression and the ability of the endothelium to capture monocytes under shear flow. Monocyte activation, CD11b-dependent adhesion, and monocyte recruitment under shear flow conditions were perturbed by the trimeric particles. Our data suggest that trimeric rHDL particles can be constructed without any loss of function, preserving the anti-inflammatory effects of HDL that are key to its in vivo actions.