Intracerebral hemorrhage (ICH) is associated with high mortality and disability, and there is no widely approved clinical therapy. Poor outcome after ICH results mostly from a mass effect owing to enlargement of the hematoma and brain swelling, leading to displacement and disruption of brain structures. Cerebral mast cells (MC) are resident inflammatory cells that are located perivascularly and contain potent vasoactive, proteolytic, and fibrinolytic substances. We previously found pharmacological MC stabilization and genetic MC deficiency to be associated with up to 50% reduction of postischemic brain swelling in rats. Here, we studied the role of MC and MC stabilization in ICH using in vivo magnetic resonance imaging and ex vivo digital imaging for calculating brain edema and hematoma volume. In a rat ICH model of autologous blood injection into the basal ganglia, four groups of Wistar rats received either saline or sodium cromoglycate (MC stabilizer, two groups) or compound 48/80 (MC degranulator). Evaluated 24 h later, MC stabilization had resulted in highly significantly better neurologic scores (P<0.001), decrease mortality (P=0.002), less brain swelling (P<0.001), and smaller hematoma volume growth (P<0.001) compared with saline and compound 48/80. Moreover, to support our hypothesis, we induced ICH in MC-deficient rats and their wild-type littermates (WT). MC-deficient rats responded with significantly better neurologic scores (P<0.001), decrease mortality (0% versus 25%), less brain swelling (P<0.05), and smaller hematoma growth (P<0.05) than WT. The role of MC deserves a close evaluation as a potential target in the development of novel forms of ICH therapy.