High density lipoproteins (HDL) can be separated into distinct particles based on apolipoprotein (apo) content. The present study compares the in vivo metabolism of the apoE-containing HDL particles LpE, LpE:A-I and LpE:A-I:A-II. The particles were purified from plasma by immunoaffinity chromatography and had alpha-mobility on agarose and 2D gel electrophoresis. The cholesteryl ester/free cholesterol and phospholipid/total cholesterol ratios in the apoE-containing particles were 0.7 and 1.0 for LpE, 1.4 and 1.1 for LpE:A-I, and 1.8 and 1.2 for LpE:A-I:A-II, respectively. Radiolabeled apoE was reassociated with the particles and the particles were injected into normolipidemic volunteers: 125I-LpE and 131I-LpE:A-I:A-II (n=3), 125I-LpE:A-I and 131I-LpE:A-I:A-II (n=3) and 125I-LpE and 131I-LpE:A-I (n=2). Fractional catabolic rates (FCR) for LpE, LpE:A-I and LpE:A-I:A-II were 3.4""""""""0.4d-1, 3.1""""""""0.3d-1 and 2.7""""""""0.4d-1, respectively (p=0.01 for LpE vs. LpE:A-I:A-II). The apoE-containing HDL particles were catabolized much more rapidly than are apoA-containing HDL particles, LpA-I (FCR 0.232d-1) and LpA-I:A-II (FCR 0.195d-1). Immunoaffinity chromatography showed that LpE:A-I particles were converted to LpE:A-I:A-II particles, whereas there was no apparent metabolic conversion of LpE and LpE:A-I:A-II. FPLC and ultracentrifugation analyses revealed that after injection there was a decrease in the percentage of radioactivity in HDL and an increase in VLDL, for up to 8 hours, coinciding with the post-prandial state of the subjects. At later timepoints the proportion of radioactivity in HDL increased. In conclusion: 1) ApoE-containing HDL particles are catabolized more rapidly than apoA-containing HDL, with LpE>LpE:A-I>LpE:A-I:A-II >> LpA-I>LpA-I:A-II. 2) The presence of apoE dramatically changes the metabolic pathways of lipoprotein particles within HDL.