Histamine is a major neurotransmitter for regulation of neuronal and vascular functions. Several studies found that histamine H₂ receptor agonists alleviated neuronal damage after brain injury. In this study, we investigated the effects of amthamine, a selective H₂ receptor agonist for cerebrovascular damage after traumatic brain injury (TBI). To prepare TBI model, mice (male ddY, 7 weeks) were given a fluid percussion injury (FPI) by hydraulic impact on the dura mater. The cerebrovascular damage was evaluated by Evans blue extravasation in mouse cerebrum. Amthamine (20-500 nmol/day) was administrated into lateral cerebroventricle from 3 hours to 3 days after FPI. Expressions of histamine H₂ receptor were evaluated by western blot and immunohistochemistry. Expressions of mRNAs for angiopoietin-1 (ANG-1) and sonic hedgehog (SHH), vascular protective factors were determined by Real-time PCR. The administrations of amthamine alleviated the Evans blue extravasation after FPI. Moreover, amthamine accelerated mRNA expressions of ANG-1 and SHH in mouse cerebrum. Expressions of histamine H₂ receptor were observed in astrocytes and brain endothelial cells. Amthamine (2-200 mM) promoted ANG-1 and SHH productions in cultured astrocytes, and increased ANG-1 expression in bEnd.3 cells (brain endothelial cells). These results suggest that histamine H₂ receptor agonist alleviates TBI-induced cerebrovascular damage by increase of vascular protective factors.