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Introduction: The role of HDL in CVD risk is not fully understood. Hypothesis: We tested the hypothesis that HDL functions are significantly associated with HDL subpopulation profile. Methods: Lipoproteins, including apoA-I-containing HDL particles, cell-cholesterol efflux (Global, ABCA1- and SRB1-mediated) and HDL Inflammatory Index were measured in a total of 289 subjects. These included 60 CHD patients, 109 subjects with either abnormal lipids (high triglycerides/low HDL or elevated β-sitosterol) or increased levels of the inflammatory markers C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, or myeloperoxidase (MPO), as well as 120 controls. Results: Global efflux was highly correlated with ABCA1-mediated efflux (r=0.921). Cholesterol efflux via the ABCA1 pathway was significantly correlated with small prebeta-1 HDL particles (r=0.762). CHD patients had significantly higher preβ-1 level than controls; however, per-particle prebeta-1 HDL effluxed 41% less cholesterol in CHD patients as compared to controls, resulting in no significant difference in overall efflux capacity between cases and controls. Cholesterol efflux via the SRB1 pathway was significantly correlated with large α-1 (r=0.784) and α-2 (r=0.460) HDL particles. These two large HDL particles effluxed about 82% of cell cholesterol via the SRB1 pathway. There was no significant difference in SRB1-mediated cholesterol efflux between CHD cases and controls. The HDL Inflammatory Index (HII) was significantly higher (unfavorable) in CHD cases than in controls and was significantly (inversely) associated with α-2 HDL particles (r=454). Increased levels of β-sitosterol significantly altered the HDL subpopulation profile and increased HII. Moreover, HII was not correlated with the concentrations of CRP, SAA, fibrinogen and MPO. Conclusion: HDL subpopulation profile is a major determinant of HDL’s overall cholesterol-efflux capacity. Efflux capacity of preβ-1 particles are compromised in CHD patients by yet unknown factor(s). HDL Inflammatory Index correlates with HDL subpopulation profile, but not with markers of inflammation in plasma.