High-density lipoprotein (HDL) containing apo A-I but no apo A-II (LpA-I) can promote cholesterol efflux from cells, while HDL containing apo A-I and apo A-II can not. Pre beta1-HDL, a minor fraction of LpA-I, is the initial acceptor of cellular cholesterol. To determine whether the pre beta1-HDL:LpA-I ratio is constant in human plasma, we measured LpA-I levels by differential electroimmunoassay, and HDL subfraction levels by nondenaturing 2-dimensional gel electrophoresis in 26 subjects. We found that the pre beta1-HDL:LpA-I ratio was higher in hypercholesterolemia (0.21+/-0.09; n = 11, P < 0.05), coronary artery disease (0.26+/-0.13; n = 5, P = 0.08) and hypertriglyceridemia (0.39+/-0.22; n = 3, P = 0.16) than in normolipidemia (0.11+/-0.03, n = 5). LpA-I levels were significantly correlated with HDL2b (r = 0.771, P=0.000001), HDL2a (r = 0.438, P < 0.01), and pre beta2-HDL levels (r = 0.496, P < 0.005) but not with pre beta1-HDL or HDL3 levels. In conclusion, the pre beta1-HDL:LpA-I ratio is not constant in human plasma. These findings strongly suggest that size distribution of LpA-I may change in various disorders.