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Our objective was to evaluate the associations of individual apolipoprotein A-I (apoA-I)-containing HDL subpopulation levels with ABCA1- and scavenger receptor class B type I (SR-BI)-mediated cellular cholesterol efflux. HDL subpopulations were measured by nondenaturing two-dimensional gel electrophoresis from 105 male subjects selected with various levels of apoA-I in preβ-1, α-1, and α-3 HDL particles. ApoB-containing lipoprotein-depleted serum was incubated with [3H]cholesterol-labeled cells to measure efflux. The difference in efflux between control and ABCA1-upregulated J774 macrophages was taken as a measure of ABCA1-mediated efflux. SR-BI-mediated efflux was determined using cholesterol-labeled Fu5AH hepatoma cells. Fractional efflux values obtained from these two cell systems were correlated with the levels of individual HDL subpopulations. A multivariate analysis showed that two HDL subspecies correlated significantly with ABCA1-mediated efflux: small, lipid-poor preβ-1 particles (P = 0.0022) and intermediate-sized α-2 particles (P = 0.0477). With regard to SR-BI-mediated efflux, multivariate analysis revealed significant correlations with α-2 (P = 0.0004), α-1 (P = 0.0030), preβ-1 (P = 0.0056), and α-3 (P = 0.0127) HDL particles.These data demonstrate that the small, lipid-poor preβ-1 HDL has the strongest association with ABCA1-mediated cholesterol even in the presence of all other HDL subpopulations. Cholesterol efflux via the SR-BI pathway is associated with several HDL subpopulations with different apolipoprotein composition, lipid content, and size.