Heart attacks frequently occur in normolipidemic subjects with low concentration of high density lipoproteins (</=35 mg/dL). A low-fat diet is generally recommended to patients with coronary heart disease. A low-fat diet decreases both low density (LDL) and high density lipoproteins (HDL). We have shown that on an Average American Diet, subjects with different HDL-cholesterol (HDL-C) levels have different HDL subpopulation profiles. In low HDL-C subjects (</=35 mg/dL), the apoA-I-only subpopulation alpha(1) is significantly decreased compared to individuals with normal HDL-C levels (>35 mg/dL). We hypothesized that as subjects with low HDL-C already have low HDL concentrations, the major decrease of HDL-C will occur in subjects with normal HDL-C when a low-fat diet is consumed. Normolipidemic male subjects consumed three diets differing in total fat and saturated fat composition (AAD: 37%, Step-1: 28%, Step-2: 24% total fat) for 6 weeks in a three-period double-blind randomized crossover design. Plasma lipids and apolipoproteins were determined and changes in distribution of HDL subpopulations were evaluated. As a result of a low-fat diet, low HDL-C individuals slightly decreased their HDL-C, but substantially decreased their LDL-C resulting in a significant improvement in the LDL-C/HDL-C ratio. However, subjects with normal HDL-C levels decreased both their LDL-C and HDL-C resulting in an unchanged LDL-C/HDL-C ratio. We also observed significant differences in response to low-fat diets in HDL-C and alpha(1) concentrations between low and normal HDL-C subjects. In the normal HDL-C group, consumption of a low-fat diet also resulted in redistribution of apoA-I-containing HDL subpopulations, indicated by a decrease in the large apoA-I-only alpha(1) subpopulation. These data demonstrate that male subjects with low HDL-C respond to a low-fat diet differently than individuals with normal HDL-C.