AIM: To determine the effect of endogenous histamine on transient forebrain ischemia-induced neuronal injury at the late phase of reperfusion using histidine decarboxylase knockout (HDC-KO) mice. METHODS: Wild-type (WT) and HDC-KO mice were subjected to bilateral common carotid artery occlusion for 30 min followed by 3 d or 15 d of reperfusion. At different time points after reperfusion, the body weight, mortality rate, learning and memory in fear conditioning test and hippocampal CA1 neuronal density were evaluated. RESULTS: At 1 d after reperfusion, the body weight loss was observed in both WT and HDC-KO mice. At 4 d, 5 d, 6 d and 7 d after reperfusion, the increment in the body weight of the HDC-KO mice was significantly smaller than that of the WT mice. During the period between 8 d and 14 d after reperfusion, the mortality rate of the HDC-KO mice was higher than that of the WT mice (P<0.05). At 14 d after reperfusion, the HDC-KO mice exhibited more aggravated deficits in contextual and cue memory compared with the WT mice. Correspondingly, a more severe CA1 neuronal injury in the HDC-KO mice than that in the WT mice was observed at 15 d but not at 3 d after reperfusion (P<0.05). CONCLUSION: Endogenous histamine may attenuate learning/memory deficits and neuronal injury at the late phase of ischemia/reperfusion. However, the involved mechanisms need to be further investigated.