Phagocytic uptake of opsonized RBCs is faster with CD47 inhibition but fastest for rigid RBCs. Human-derived THP-1 macrophages were incubated with human RBCs that were opsonized with anti-hRBC antiserum and also (A) blocked with anti-CD47, (B) native RBCs with active CD47⁺, or (C) rigidified as GA discocytes. Time-lapse imaging in DIC and phase contrast begins with initial adhesion between macrophage and RBC targets and ends on complete engulfment (scale bar, 8 μm). At the right of each time-lapse series, silhouettes of the target RBC clarify the changes in RBC morphology over the course of engulfment and RBC position relative to the macrophage boundaries, as indicated by the sketched lines (C, fourth panel, inset) GA discocytes are often enclosed in a spacious phagosome that shows gaps between the discocyte and phagosome membranes. (D) The projected length (L_p) of the engulfed RBC was quantified along the phagocytosis axis (schematic, top left) and shows that phagocytic deformation is fast and classically vectored inward for rigid RBCs and for CD47-blocked RBCs compared with native RBCs (n ≥ 3 ± SD). When CD47 can signal self, phagocytosis is much slower, and L_p often increases (up to 1.5-fold L_p0). (E) The percentage of classical uptake events for each RBC treatment is plotted vs the time required to complete engulfment, with the frequency of classical uptake showing a negative linear correlation with engulfment time (line fit, R² = 1.0). Nonclassical uptake is most frequently observed with native RBCs that signal self and deviates from the classical trend by at least twofold.