In this paper we hypothesize a novel mechanism by which brain injury occurs after intracerebral hemorrhage. We propose the following mechanism: (1) heme that is derived from extravasated erythrocytes is degraded into bilirubin and bilirubin oxidation products (BOXes). (2) Bilirubin and BOXes activate microglia and astrocytes, which are cells with immune functions in the brain. This activation leads to release of cytokines and activation of leukocyte adhesion molecules on the luminal surface of cerebral endothelial cells. (3) Leukocytes then traffic into the brain. (4) Leukocytes, activated glial cells and cytokines contribute to injury processes. We present preliminary data in support of our hypothesis that BOXes activate glia.