Various stressful stimuli cause mast cell degranulation. Hemorrhagic shock is one such stressful stimulus which may cause mast cell degranulation and histamine release. Histamine may be involved in the pathophysiology of hemorrhage. It was reported that there are large amounts of histamine in the anterior and posterior lobes of the pituitary and the adjacent median eminence of the hypothalamus. Most of the histamine in the posterior pituitary is in mast cells. In addition, both vasoactive intestinal peptide (VIP) and histamine-containing neurons are available in the hypothalamus. It therefore seems reasonable to suppose that these three systems (i.e., mast cells, VIP-containing neurons, and histamine-containing neurons) may play an important role in the progression of hemorrhagic shock. 66 albino rats (200-250 g) of either sex were used. The presence of mast cells was examined by light microscopy. Hemorrhage caused mast cell degranulation in a correlation with the amount of blood loss. In all cases, the most intense degranulation was observed in the hypothalamus, especially the nucleus arcuatus, and in the subcutaneous tissue. The intensity of degranulation gradually decreased in the peripheral blood vessel, peritoneum and omentum, in this order. VIP prevented degranulation, but aprotinin and H-1 and H-2 receptor blockers did not.