CD59 (protectin) is a glycophosphoinositol (GPI) lipid-anchored inhibitor of complement lysis that is expressed on the membranes of blood cells, endothelial cells, epithelial cells and cardiomyocytes. CD59 may be shed from cell surfaces, e.g. during cell injury, but when entering human plasma its fate is unknown. In this study we observed that radiolabelled lipid-anchored CD59, but not soluble urinary CD59 without anchor lipid, incorporated into high-density lipoprotein (HDL) particles when mixed with human serum and analysed by high resolution gel filtration and anti-apoA-I affinity chromatography. Only a small proportion of CD59 entered the low-density lipoprotein (LDL) fraction. HDL particles were capable of incorporating 25-42% of [125I]CD that was preinserted into the membranes of rabbit erythrocytes (RaE) and transferred 7-14% of [125I]CD59 back to RaE or to cultured human endothelial cells (EA.hy 926). Immunoaffinity purification and immunoblotting analysis demonstrated that HDL isolated from normolipidemic human serum contained small amounts of CD59. These results suggest that HDL particles could be involved in the recycling of GPI lipid-anchored molecules released from cell surfaces.