The purpose of this study was to investigate the effect of oxygen-glucose deprivation (OGD) on degranulation and histamine release of mast cells. Cultured mast cells were exposed to OGD for 1, 2, 4, 8, or 16 h. At 2 h of OGD exposure, the degranulation percentage of mast cells had increased and subsequently showed a progressive further increase, associated with a similar change in lactate dehydrogenase release. Histamine release increased significantly from 1 h of OGD exposure. These results indicate that OGD induces mast cells to degranulate, possibly via a cytotoxic response. This in vitro ischemic model of mast cells might clarify their roles in the pathological processes induced by cerebral ischemia.