The effect of human arterial proteoglycans (PG1) on the interaction of low density lipoprotein (LDL) with cultured human monocyte-derived macrophages (HMDM) was studied. LDL was insolubilized by treatment with chondroitin-6-sulfate-rich, partially purified PG1. The LDL, resolubilized in culture medium, was added to HMDM. The PG1 pretreated LDL induced lipid accumulation in the HMDM, converting them into foam cells. Mass determination of lipids by spectrophotometric and chromatographic procedures showed a 2-4-fold accumulation of triglycerides, phospholipids, unesterified cholesterol and cholesterol esters in 48 h, in the HMDM incubated with PG pretreated LDL, when compared to those incubated with native LDL. Incorporation of [14C]oleic acid into the HMDM lipid esters correlated with the accumulation. Association of 125I-labeled LDL and of fluorescent labeled LDL (3,3-octadecyl indocarbocyanine) to HMDM also indicated that the PG1-pretreatment of LDL increased its uptake. Density gradient centrifugation, isoelectric focusing and electron microscopy showed that, when added to the cells, the PG1 pretreated LDL was not aggregated or altered in its surface charge. However, controlled trypsin treatment and polypeptide pattern analysis indicate that the accessibility of apoB has been altered. The results suggest that changes in the surface of LDL, induced by the arterial PG1, lead to increased endocytosis of the lipoprotein and stimulation of lipid synthesis in the macrophages. The possibility that a similar process may cause lipid accumulation in arterial macrophages is discussed.