Human xanthomas derived from four subjects with familial hypercholesterolemia (3 homozygotes and 1 heterozygote) were studied by immunohistochemical methods to determine the presence and distribution of lipoproteins, which have been implicated in the pathogenesis of atherosclerosis. Oxidatively modified low-density lipoprotein (OxLDL) epitopes detected with anti-OxLDL monoclonal antibodies, appeared to have a similar distribution in xanthomata to that of macrophages, detected by a cell-specific monoclonal antibody. Double antibody labeling with both an anti-macrophage antibody and an anti-OxLDL antibody demonstrated that OxLDL epitopes are associated with macrophages and occurred intracellularly. Low-density lipoprotein (LDL) epitopes were detected extracellularly, with a distribution that was different from that of OxLDL. In addition, apo(a) epitopes detected by an apo(a) specific monoclonal antibody, had a distribution similar to that of LDL in the dermis and subcutaneous tissues. The observed epitope distribution of LDL, OxLDL, or apo(a) was the same regardless of the method of treatment of the patients from whom the xanthomas were obtained (probucol, simvastatin, LDL apheresis). These findings suggest that OxLDL is likely to play a pathogenetic role in the lipid accumulation by macrophages in xanthomas, and suggest that Lp(a) also may play a role in their pathogenesis.