Turks have strikingly low levels of high density lipoprotein cholesterol (HDL-C) (10-15 mg/dL lower than those of Americans or Western Europeans) associated with elevated hepatic lipase mass and activity. Here we report that Turks have low levels of high density lipoprotein subclass 2 (HDL(2)), apoA-I-containing lipoproteins (LpA-I), and pre-beta-1 HDL and increased levels of HDL(3) and LpA-I/A-II particles (potentially an atherogenic lipid profile). The frequency distributions of HDL-C and LpA-I levels were skewed toward bimodality in Turkish women but were unimodal in Turkish men. The apoE genotype affected HDL-C and LpA-I levels in women only. In women, but not men, the varepsilon2 allele was strikingly more prevalent in those with the highest levels of HDL-C and LpA-I than in those with the lowest levels. The higher prevalence of the epsilon2 allele in these subgroups of women was not explained by plasma triglyceride levels, total cholesterol levels, age, or body mass index. The modulating effects of apoE isoforms on lipolytic hydrolysis of HDL by hepatic lipase (apoE2 preventing efficient hydrolysis) or on lipoprotein receptor binding (apoE2 interacting poorly with the low density lipoprotein receptors) may account for differences in HDL-C levels in Turkish women (the epsilon2 allele being associated with higher HDL levels). In Turkish men, who have substantially higher levels of hepatic lipase activity than women, the modulating effect of apoE may be overwhelmed. The gender-specific impact of the apoE genotype on HDL-C and LpA-I levels in association with elevated levels of hepatic lipase provides new insights into the metabolism of HDL.