Extracorporeal reduction of plasma low density lipoproteins (LDLs) by LDL apheresis was shown to attenuate the proatherogenic influences of LDL, such as impairment of vasodilation and increased monocyte adhesion to the endothelium. In 16 patients with familial hypercholesterolemia, we analyzed whether LDL apheresis by the heparin precipitation procedure affected the oxidative resistance of LDL. Plasma LDL cholesterol concentrations were reduced by 65% after the apheresis. The lag time of copper-mediated LDL oxidation was increased from 103 to 117 minutes (P<0.0005). The LDL contents of alpha-tocopherol and beta-carotene, as well as the ratio of monounsaturated to polyunsaturated fatty acids in LDL, were not altered. However, the LDL apheresis induced a 15% increase in the LDL contents of plasmalogen phospholipids (P<0.0005), a class of ether phospholipids that were recently shown to prevent lipid oxidation. The phosphatidylcholine (PC) to lysoPC ratio was elevated by 16% after the apheresis (P<0.0005). The percent increase in LDL plasmalogen phospholipids showed a close association with the increased lag time after apheresis (P<0.0005). The LDL plasmalogen contents of the blood samples from patients and from normolipidemic donors were also positively related to the lag time (P<0.005). In vitro loading of LDL with plasmalogen phospholipids resulted in a prolongation of the lag time and an increase in the PC/lysoPC ratio. In conclusion, the rapid rise in LDL contents of plasmalogen phospholipids most probably causes the increase in lag time after LDL apheresis. Plasmalogens appear to play an important role in the oxidation resistance of LDL in vivo.