Apolipoprotein E4 (apoE4) is a positively charged proinflammatory apolipoprotein bound to high-density lipoprotein (HDL) cholesterol and remnant lipoproteins. ApoE4 is associated with an increased risk of cardiovascular and cerebrovascular disease. Low-density lipoprotein (LDL) apheresis, a therapy for patients with familial hypercholesterolemia, removes apolipoprotein B and other positively charged plasma proteins but negatively charged proteins such as HDL cholesterol are generally spared. Despite their negative charge, LDL apheresis still removes 10% to 15% of HDL cholesterol, in particular, inflammatory HDL cholesterol. Patients with familial hypercholesterolemia have increased plasma levels of apoE4 and apoE4-bound HDL cholesterol. We tested the hypothesis that LDL apheresis would reduce the plasma levels of apoE4. We analyzed the plasma apoE4 levels using enzyme-linked immunosorbent assay immediately before and after LDL apheresis in 10 patients with familial hypercholesterolemia who had tested positive for the apoE4 isoform. After one treatment, the mean plasma apoE4 levels had been reduced by 39%, LDL cholesterol by 75%, triglycerides by 38%, and HDL cholesterol by 18%. The change in HDL cholesterol was significantly related to the apoE4 baseline values (r = −0.83, p = 0.001) and apoE4 levels after apheresis (r = 0.816, p = 0.004). In conclusion, LDL apheresis acutely reduced the plasma levels of apoE4. The mechanism of apoE4 reduction by LDL apheresis might be related to the selective reduction of a particular HDL cholesterol.