Cell death is indispensable for tissue homeostasis and is a fundamental principle of inflammation and lymphocyte generation. Rapid removal and destruction of cellular corpses is critical and insufficient removal may lead to the release of cellular content into the environment. These immunogenic “host-self” molecules might induce a pro-inflammatory response, autoantibody formation, and development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Nucleosomes might also function as endogenous danger signals. Recently, the plasma serine protease factor VII-activating protease (FSAP) was shown to release nucleosome from late apoptotic cells. We investigated the mechanism of nucleosome release and its regulation. We studied FSAP activation and discuss the possible role of FSAP in health and disease. Our data show that FSAP is able to remove nucleosomes from necrotic cells as well as late apoptotic cells. The nucleosome removal from necrotic cells occurs in cooperation with DNase I. We set up assays to measure FSAP complexes with its inhibitors in plasma as indirect method to screen for FSAP activation. FSAP is activated in patients with several inflammatory conditions and levels of FSAP-inhibitor complexes correlate with nucleosome levels and severity of disease. FSAP activation may thus serve as a sensor for cell death in circulation. We have further shown that serum from a subset of SLE patients displays an impaired nucleosome releasing activity. We envisage that impaired nucleosome release may in turn result in persistence of the nucleosomes in the circulation leading to a vicious cycle of more anti-nucleosome autoantibodies and exacerbation of the disease.