Nucleosomes are major autoantigens in systemic lupus erythematosus. These are found as circulating complexes in both lupus patients and lupus mice. The existence of a potential ubiquitous cell surface receptor specific for nucleosomes has been suggested. However, neither the nature nor the role of this receptor has been identified. Moreover, the consequence of receptor-nucleosome interaction on the target cell has not been studied in detail so far. We show here that purified nucleosomes induce cell death of normal and lupus lymphocytes ex vivo in a dose- and time-dependent manner whereas human dendritic cells were relatively resistant. Most importantly, nucleosome-induced cell death is primary necrosis. Moreover, necrosis could be abolished when nucleosomes were first treated with deoxyribonuclease I, proteinase K or with a specific monoclonal antibody. Finally, intravenous injections of purified nucleosomes result in a reduced spleen cell number compared to buffer-injected mice, indicating that circulating nucleosomes may behave similarly in vivo. Taken together, this is the first report indicating that nucleosomes are able to induce necrosis,which in turn could result in an amplification loop of the disease causing the inflammation observed in lupus patients.