This study examines the role of the reticuloendothelial system in the metabolism and tissue uptake of chemically modified human low density lipoprotein (LDL) in rabbits. Treatment with 1,2-cyclohexanedione or HCHO/NaBH4 abolishes receptor-mediated catabolism of the lipoprotein and restricts its clearance to receptor-independent pathways. When the plasma clearances of the two modified lipoproteins were measured in rabbits the 1,2-cyclohexanedione-treated LDL was removed 19% faster (P less than 0.001) than HCHO/NaBH4-treated LDL. This was associated with an increased uptake of 1,2-cyclohexanedione-treated LDL over HCHO/NaBH4-treated LDL into tissues, particularly the liver and spleen, suggesting that their differential clearance may have involved the reticuloendothelial system. To examine this possibility the experiment was repeated in animals whose reticuloendothelial activity had been suppressed by injections of an ethyl oleate emulsion. This reduced the difference in the plasma clearance rates of 1,2-cyclohexanedione-treated LDL and HCHO/NaBH4-treated LDL and virtually abolished their differential tissue uptakes, adding weight to the proposal that the reticuloendothelial system may be involved in the receptor-independent catabolism of LDL.