Increased endothelial permeability to low-density lipoprotein (LDL) is believed to be an initiating factor for atherosclerotic lesions. Concentrations of LDL, alpha 2-macroglobulin and albumin were measured by immunoassay in interstitial fluid collected from normal intima and atherosclerotic lesions of human aortas. The concentration of LDL in interstitial fluid from normal intima was twice the concentration in the patient's serum. In early proliferative (gelatinous) lesions the amount of interstitial fluid was consistently increased but its LDL concentration varied between 80 and 200% of adjacent normal intima. Highest concentrations of LDL were found in interstitial fluid from more advanced proliferative lesions, but the amount was reduced, suggesting a shift in tissue water. LDL was consistently low in interstitial fluid from fatty streaks comprised of lipid-filled cells, and in four of 12 lesions it was absent although alpha 2-macroglobulin and albumin concentrations were normal. Electrophoretic mobility of LDL, reflecting surface charge, was unchanged or increased in interstitial fluid from normal intima and fatty streaks, but decreased in gelatinous lesions. The ratio of LDL to alpha 2-macroglobulin and albumin in interstitial fluid was higher than in adjacent intact tissue. The results do not support the idea that increased endothelial permeability to LDL initiates atherogenesis.