Apolipoprotein (apo) M is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL-receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL-receptor mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of 3 different LDL-receptor mutations (n=9) or the apoB3500 mutation (n=12). These carriers had increased plasma apoM (1.34±0.13 µmol/L, P=0.003, and 1.23±0.10 µmol/l, P=0.02, respectively) as compared with non-carriers (0.93±0.04 µmol/L). When we injected human apoM-containing HDL into Wt (n=6) or LDL-receptor deficient mice (n=6), the removal of HDL-associated human apoM was delayed in the LDL-receptor deficient mice. After 2 hrs 54±5% versus 90±8% (P <0.005) of the initial amounts of human apoM remained in plasma of Wt and LDL-receptor deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r=-0.38, P=0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL-receptor mediated clearance of apoB-containing particles.