Studies with animal models suggest that saturated fatty acids raise low density lipoprotein (LDL)-cholesterol levels by reducing LDL receptor-mediated clearance. To examine this directly in humans, we studied the effects of lowering dietary saturated fat on LDL-receptor abundance in peripheral mononuclear cells which reflects hepatic LDL-receptor status. Healthy males and females (n = 25) participating in the DELTA (Dietary Effects on Lipoproteins and Thrombogenic Activity) Study consumed three experimental diets in a randomized cross-over design. Diets provided 34% fat, 15% saturated fatty acids (Average American Diet); 29% fat, 9% saturated fatty acids (Step-One Diet); and 25% fat, 6% saturated fatty acids (Low SAT Diet). Peripheral mononuclear cells were isolated from blood samples collected after 6 and 8 wk. An ELISA was used to quantify LDL-receptor protein in total cell membranes. LDL-receptor abundance increased by 10.5% after the Low SAT Diet (P < 0.05). This was associated with an 11.8% decrease in serum LDL-cholesterol (P < 0.05). A linear inverse relationship was observed between the percentage change in LDL-cholesterol and the percentage change in LDL-receptor abundance (r = -0.59; P < 0.01). In addition, LDL-receptor abundance also was correlated inversely (P < 0.001) with serum levels of LDL-cholesterol (r = -0.747) and apoB (r = -0.593). In summary, reducing dietary saturated fat is associated with an increase in LDL-receptor abundance of magnitude similar to the decrease in serum LDL-cholesterol. Thus, an important mechanism by which reductions in dietary saturated fatty acids decrease LDL-cholesterol in humans is through an increase in LDL-receptor number.