In the present study, we sought evidence for a surface nucleosome receptor in the fibroblastic cell line CV‐1, and questioned whether anti‐double‐stranded (ds)DNA and/or anti‐histone autoantibodies could recognized and influence the fate of cell surface‐bound nucleosomes. ¹²⁵I‐labeled mononucleosomes were shown to bind to the cell layer in a specific, concentration‐dependent and a saturable manner. Scatchard analysis revealed the presence of two binding sites: a high‐affinity site with a Kd of ∼ 7nM and a low‐affinity site (Kd ∼ 400 nM) with a high capacity of 9 × 10⁷ sites. Visualization of bound mononucleosomes by fluorescence revealed staining on both the cell surface and the extracellular matrix (ECM). Purified mononucleosome‐derived dsDNA (180–200 bp) was found to compete for binding of ¹²⁵I‐mononucleosomes on the low‐affinity site, to stain exclusively the ECM in immunofluorescence, and to precipitate three specific proteins of 43, 180 and 240 kDa from ¹²⁵‐I‐labeled cell lysates. Nucleosomes were found to precipitate not only the 180‐kDa dsDNA‐reactive component, but also a unique protein of 50 kDa, suggesting that this protein is a cell surface receptor for nucleosomes on these fibroblasts. Once bound on the cell surface, mononucleosomes were recognized and secondarily complexed by lupus anti‐dsDNA or anti‐histone antibodies (i.e. anti‐nucleosome antibodies), thus forming immune complexes in situ. The presence of these complexing auto‐antibodies was found dramatically to enhance the kinetics of mononucleosome internalization. Following the internalization of the nucleosome‐anti‐nucleosome complexes by immunofluorescence, we observed the formation of vesicles at the edge of the cells by 5–10 min which moved toward the perinuclear region by 20–30 min. By means of double‐fluorescence labeling and proteolytic treatment, these fluorescent vesicles were shown to be in the cytoplasm, suggesting true endocytosis of nucleosome‐anti‐nucleosome immune complexes. As shown by confocal microscopy, at no stage of this endocytic process was there any indication that coated pits or coated vesicles participated. Co‐distribution of the endocytic vesicles with regions rich in actin filaments and inhibition of endocytosis of nucleosome‐anti‐nucleosome complexes by disruption of the micro‐filament network with cytochalasin D suggest a mechanism mediated by the cytoskeleton. Taken together, our data provide evidence for the presence of a surface nucleosome receptor. We also show that anti‐dsDNA and anti‐histone antibodies can form nucleosome‐anti‐nucleosome immune complexes in situ at the cell surface, and thus dramatically enhance the kinetics of nucleosome endocytosis.