Antibodies against nucleosomes are a serological hallmark of systemic lupus erythematosus (SLE). Apoptotic cells are the unique source of nucleosomes, which are formed through cleavage of chromatin by nucleases. These nucleosomes and other autoantigens targeted in SLE are expressed in apoptotic blebs or at the surface of apoptotic cells. Therefore, it is conceivable that circulating antibodies can influence apoptotic cell clearance. Using an in vitro phagocytosis assay, we analysed the phagocytic efficacy for apoptotic cells of resident peritoneal macrophages from pre-morbid and diseased lupus mice. The assay was carried out in the presence of autologous serum, using autologous apoptotic thymocytes as targets. Under these conditions macrophages from diseased MRL/lpr and NZBxNZW(F1) lupus mice, and from age-matched NZB mice showed a decreased phagocytic efficacy (decrease 47%, 48% and 37%, respectively compared to measurements in pre-morbid mice). The cause of this decrease resides in the serum, and is not due to an acquired defect of macrophages. In conclusion, during disease progression in murine SLE, apoptotic cell clearance becomes impaired, which might amplify further disease progression.