BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome that involves loss of macrophages' self-cells recognition resulting in auto-phagocytosis of erythrocytes, leukocytes, and platelets and leading to multi-system effects. The pathogenesis of HLH is unclear but can be explained by malfunction of the physiologic inhibitory pathway through interaction between macrophage SIRP-alpha and erythrocyte CD 47. The goal of the present study was to evaluate if erythrocytes phagocytosis occurs as a result of altered macrophage SIRP-alpha expression during inflammatory/stressful conditions as seen in HLH. MATERIAL AND METHODS RAW264.7 macrophages were cultured in serum-free media (SFM) and complete media (CM) to simulate stressful and physiologic conditions, respectively. CD47+ mouse erythrocytes were used to test interactions with macrophages at different stages. SIRP-alpha expressions and phagocytosis assays were measured and analyzed at different steps. The study was in vitro and used murine cells to simulate in vivo human interactions. RESULTS SIRP-alpha expressions and phagocytosis rates were higher in SFM compared to CM. Interestingly, after adding SIRP-alpha blocking antibodies (Ab), phagocytosis rates significantly decreased. CONCLUSIONS Serum deprivation and LPS/INF-Gamma induction resulted in increased SIRP-alpha expression and erythrophagocytosis. Using SIRP-alpha Ab during this condition decreased the rate of erythrophagocytosis, which indicates that SIRP-alpha receptor can have pro-phagocytic activity.