Vascular amyloidosis in Alzheimer's disease (AD) results in the exposure of red blood cells to β-amyloid fibrils (Aβ). The potential in vivo ramifications of this exposure have been investigated by injecting Aβ1–40 alone or Aβ-bound mouse red blood cells into the circulation of C57BL/6 mice. Results indicate that when Aβ1–40 is injected alone, a transient uptake of the fibrils by red blood cells occurs in vivo. When Aβ-bound red blood cells were injected, β-amyloid is rapidly removed from these cells in vivo. Double-labeling experiments indicate that while some of the red blood cells bound to Aβ1–40 are removed from circulation, a major fraction of these cells remain in circulation even after Aβ is removed. Immunohistochemistry of murine tissue samples obtained after sacrificing the animals suggests that within 1 h after injection of Aβ1–40 or Aβ-bound red blood cells, Aβ is found in spleen phagocytes and liver Kupffer cells. Heme staining further indicates that the binding of Aβ1–40 to red blood cells enhances red cell phagocytosis by the spleen.