Belimumab, on top of background Systemic Lupus Erythematosus (SLE) standard therapy, is effective in reducing SLE disease activity and preventing lupus flares, which was confirmed in “BLISS trials”. The mechanisms involved in preventing lupus flare by belimumab remain largely unknown. We aimed to explore the response of PBMCs from lupus patients under belimumab treatment to the apoptotic cells. PBMCs, obtained from five lupus patients with disease flare treated with belimumab, were coincubated with the apoptotic cells induced from Jurkat cells treatment. After incubation, the cells were harvested for surface markers analysis by flow cytometry and the supernatants were tested for cytokines assayed by ELISA kits. Before belimumab treatment, Peripheral Blood Mononuclear Cells (PBMCs) from lupus patients showed markedly secretion of Interferon-α (IFNα) and Interleukin-6 (IL-6) in response to the apoptotic cells. After belimumab treatment, lupus PBMCs were characterized by significant reduction of IFNα secretion (P=0.0103) upon recognition of the apoptotic cells. Reduced activation was also observed in lupus monocytes and T lymphocyte. Belimumab treatment suppressed response of lupus PBMCs to the apoptotic cells, which provides a fresh clue to understand mechanism other than B-cell depletion in the prevention of lupus flare.