To explore possible mechanisms whereby the triglyceride-rich lipoproteins IDL and VLDL may promote atherosclerosis, fractional loss of these lipoproteins from the intima-inner media was measured in vivo in genetically hyperlipidemic rabbits of the St Thomas's Hospital strain and compared with the fractional loss of LDL, HDL, and albumin. These rabbits exhibit elevated plasma levels of VLDL, IDL, and LDL. In each rabbit, two aliquots of the same macromolecule, one iodinated with 125I and the other with 131I, respectively, were injected intravenously on average 24 and 3 hours, respectively, before removal of the aortic intima-inner media. The fractional loss from the intima-inner media of newly entered macromolecules was then calculated. The average fractional losses for VLDL, IDL, LDL, HDL, and albumin in lesioned aortic arches were 0.1%/h (n = 4), -0.2%/h (n = 3), 1.8%/h (n = 4), 11.4%/h (n = 3), and 26.3%/h (n = 1), respectively; in nonlesioned aortic arches fractional losses for IDL, LDL, HDL, and albumin were 1.7%/h (n = 1), 0.6%/h (n = 2), 14.6%/h (n = 3), and 25.9%/h (n = 3). In both lesioned and nonlesioned aortic arches, the logarithms of these fractional loss values were inversely and linearly dependent on the diameter of the macromolecules (R2 = .57, P = .001 and R2 = .84, P < .001), as determined from electron photomicrographs of negatively stained lipoproteins. These results suggest that after uptake into the arterial intima, VLDL and IDL as well as LDL are selectively retained in comparison with HDL and albumin.