We have studied the effect of several chemical modifications to low-density lipoprotein (LDL) on its intracellular fate in macrophages. Native, acetylated and oxidized 125I-LDL were supplied to cultured peritoneal macrophages and the accumulation and distribution of labelled protein was measured both during uptake and a subsequent chase period. The intracellular accumulation of macromolecular oxidized LDL protein greatly exceeded that of acetylated LDL, despite similar rates of uptake and common endocytic receptors. The accumulation of intracellular apoprotein was proportional to the extent to which the LDL was first oxidized. ApoB of oxidized LDL was more resistant to proteolysis by lysosomal enzymes than native apoB. Interestingly, acetylated apoB is more rapidly hydrolysed than the native protein. 125I-LDL modified with 4-hydroxynonenal (HNE) and myricetin, but not with malondialdehyde (MDA), was also accumulated within macrophages in a high-molecular weight fraction, and was resistant to cell-free lysosomal proteolysis. These forms of LDL also contained crosslinked apoB molecules. It is suggested that the accumulation of oxidized LDL within macrophages may he due, at least in part, to the formation of inter- or intra-molecular crosslinks in apoB which render it less accessible to proteolysis.