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Objective To explore the potential effects of endothelial progenitor cells (EPCs)- angiogenesis on mechanism of alleviating cognitive dysfunction in rats subjected to cerebral ischemia-reperfusion (I/R) injury. Methods A total of 121 male Sprague–Dawley (SD) rats were randomly divided into four groups: Sham group (n=31), focal I/R(MCAO, 0.9% saline 10 μL, n=30) group, MCAO+Vehicle (sodium azide, 0.1% Vehicle 10 μL, n=30) group and MCAO+HPX (1.86 g/L HPX 10 μL, n=30) group. The modified neurological severity scores (mNSS) was carried out to determine neurological function deficit after I/R. Morris water maze (MWM) was carried out to assess learning and memory abilities after I/R. The circulating EPCs after I/R were counted by flowcytometry (FCM) combined with double-immunofluorescence staining of CD34 and CD133. Angiogenesis in rat penumbra cortex after I/R was assessed by immunohistochemical technique combined with immunofluorescent chromogenic detection of CD31 and vWF. Results Compared with sham group, the mNSS scores, the escape latency and the circulating EPCs count were increased after I/R, the time percentage spent in target quadrant was reduced, and the new vessel density in penumbra cortex was increased after I/R in MCAO group (P < 0.05 respectively). There were no significant differences in mNSS score, the escape latency, the time percentage spent in target quadrant, the circulating EPCs count and the new vessel density in penumbra cortex between MCAO group and MCAO+Vehicle group (P > 0.05). The mNSS score and the escape latency were significantly decreased, the circulating EPCs count and new vessel density in penumbra cortex were significantly increased after I/R in MCAO+HPX group compared with those of MCAO+ Vehicle and MCAO group (P < 0.05). Conclusion EPCs-angiogenesis signaling plays positive effects on HPX alleviating cognitive dysfunction in rats subjected to focal cerebral ischemia reperfusion injury. [ABSTRACT FROM AUTHOR]