In rabbits, the aortic arch and branch sites of the descending thoracic and abdominal aortas are susceptible to atherosclerosis. This study investigated the hypothesis that the reported focal increase in LDL concentration and mean residence time at susceptible aortic sites after feeding cholesterol for 4 to 8 days precede atherosclerotic change as indicated by increased aortic cholesterol concentration. Cholesterol concentrations for all aortic sites of normal rabbits were similar (approximately equal to 2.8 mumol/g). No change in aortic cholesterol concentration could be detected after feeding cholesterol for 8 days. However, after feeding cholesterol for 12 and 16 days, cholesterol concentrations for abdominal branch sites were increased compared with abdominal branch sites of normal rabbits (4.47 +/- 0.50, n = 8, and 4.85 +/- 0.33, n = 11, mumol/g, respectively, versus 2.87 +/- 0.27, n = 12, mumol/g; P < .025 and P < .005, respectively). In contrast, the cholesterol concentration of atherosclerosis-resistant nonbranch abdominal aorta was unchanged after feeding cholesterol for 16 days and was much less than that of the branch sites (2.72 +/- 0.12 versus 4.85 +/- 0.33, mumol/g, n = 11; P < .001). Cholesterol concentrations for other susceptible sites were also increased after feeding cholesterol for 12 and 16 days. Cholesterol concentrations for susceptible sites were linearly related to a combined measure of duration and extent of hypercholesterolemia (P < .001 to P < .0001), whereas no such relationship could be detected for resistant sites. Most (59% to 93%) of the cholesterol accumulating in susceptible aortic sites after feeding cholesterol for 12 and 16 days was nonesterified, suggesting that the increased cholesterol concentration did not reflect development of foam cells or the insudation of plasma lipoproteins. This study suggests that the reported focal increases in LDL concentration and mean residence time at susceptible aortic sites during cholesterol feeding precede atherosclerosis.