The resolution of an intracerebral hemorrhage can be measured by the occurrence of hemosiderin. Extravasation of blood elicits a cellular reaction in the adjacent surviving tissue where the lesion activates resident microglia and attracts many more phagocytes from the blood stream. The signals for this migration into the perifocal reactive zone are not fully understood but it is likely that proteins in the coagulated blood contribute to cellular activation. In order to study the role of plasma proteins in the pathogenesis of the perifocal reactive zone, intracerebral injections of either autologous whole blood (0.1 ml) or an equal volume of washed autologous red blood cells (RBC) in lactated Ringer's solution were made in adult rabbits. The amount of total iron was the same (30 micrograms). The cellular responses to the injections were studied by iron histochemistry and immunocytochemistry for ferritin, the ferritin repressor protein (FRP), the glial fibrillary acidic protein (GFAP), and the complement receptor CR3. Experimental hematomas resolved much more slowly after the injection of whole blood than after the injection of RBC. Qualitative microglial and astrocytic responses were quite similar. However, at 48 h, iron- and ferritin-reactive microglia were more numerous following the injection of whole blood. After injections of either type, ferritin-immunoreactive cells were more abundant than iron-positive cells. This observation implied that the biosynthesis of holoferritin protein and iron incorporation proceeded independently. Expression of CR3 on the surface of microglia was much more prominent after whole blood, suggesting a role of inactivated complement 3b in the attraction of additional phagocytes. Conversion to hemosiderin began at 5 days after the injection of either blood or RBC. The lesions caused initial destruction of astrocytes in the perifocal zone as judged by GFAP- and FRP-immunoreactivity. However, at 5 days, astrocytic processes reentered the perifocal zone and intermingled with microglia and macrophages. It is proposed that this contact between astrocytes and microglia reversed the uncoupling of ferritin biosynthesis and iron incorporation and initiated the storage of iron and formation of hemosiderin.