AIM: Histamine released from mast cell degranulation participates in the pathogenesis of ischemia/reperfusion injury. The purpose of our study was to define the role of histamine in hypoxia/reoxygenation mediated liver cell injury and to elucidate the underlying mechanism in vitro. METHODS: Histamine alone or in combination with H1 receptor antagonist (pyrilamine), H2 receptor antagonist (cimetidine) or H3/4 receptor antagonist (thioperamide) at different concentrations before hypoxia was added to rat liver BRL-3A cell which was subjected to 24h hypoxia followed by 4h reoxygenation. Cell proliferation, apoptosis and the changes of ultrastructure were assessed, and MDA contents, SOD activities and ALT levels were quantified as well. RESULTS: Histamine (from 10(-3) to 10(-9) M) did not affect the growth of BRL-3A cells without hypoxia treatment. However, histamine 10(-8)M significantly lowered the growth of BRL-3A cells challenged by hypoxia/reoxygenation, accompanied with concomitant elevations in MDA contents and decreases in SOD activities, all these changes were blocked by cimetidine, not by pyrilamine or thioperamide. However, histamine (above 10(-6) M) did not show exacerbating effects in BRL-3A cell subjected to hypoxia/reoxygenation. CONCLUSION: Histamine at low concentrations (10(-7)-10(-9) M) aggravates hypoxia/reoxygenation mediated BRL-3A damage through histamine H2 receptor.