Liposome encapsulated hemoglobin is being developed as an artificial resuscitative fluid for in vivo oxygen delivery. In the present report, we examine the effect of accumulation of liposome encapsulated hemoglobin on the structure of reticuloendothelial organs following administration of liposome encapsulated bovine hemoglobin in the normovolemic rat. We have also examined the administration of the liposome vehicle, tetrameric bovine hemoglobin, and liposome encapsulated bovine hemoglobin that had been lyophilized with 300 mM trehalose and rehydrated just before injection. Following injection into the tail vein, rats were sacrificed and liver, spleen, kidney, and lung harvested at 2 h, 24 h, 1 week, and 2 weeks for analysis. Gross pathologic findings of animals injected with liposome encapsulated hemoglobin showed statistically significant splenomegaly with a waxy parenchymal pallor at early time points. Microscopic findings indicate that the liver and spleen are principally involved with liposome encapsulated hemoglobin removal over the course of 24 h with transient cytoplasmic vacuolization in tissue resident phagocytes as evidenced by both light and electron microscopic examination. Presence of liposome encapsulated hemoglobin in these vacuoles was confirmed by oil red 0 and prussian blue stains. Splenic weight was observed to decline after 24 h but still remained significant above sham-treated controls at 2 weeks and could be correlated with increased hematopoietic activity. Other findings only in animals injected with lyophilized liposome encapsulated hemoglobin included transient loss of laminae rara in the basal lamina, podocyte fusion in the kidney, and small pulmonary infarcts in the lung over the course of 24 h. This latter finding may be associated with trapping of large particles or agglutinated liposome encapsulated hemoglobin. These data indicate that the administration of liposome encapsulated hemoglobin causes transient changes in the organs of the reticuloendothelial system.