Unclustered and pre-clustered ephrin-A5-Fc have identical anti-epileptic effects in the dentate gyrus of hippo campus in a mouse model of temporal lobe epilepsy (TLE), and act through alleviating ephrin receptor A4 (EphA4)-mediated neurogenesis and angiogenesis. However, the effects of ephri n-A5-Fcs on EphA4 and angiogenesis in Cornu Ammonis (CA)1 and CA3 areas remain unclear. In the present study, male C57BL/6 mice underwent pilocarpine-induced TLE. The expression of EphA4 and ephrin-A5 proteins was analyzed by immunohistochemistry, and the mean density and diameter of platelet endothelial cell adhesion molecule-l-labeled microvessels in CA1 and CA3 were calculated in the absence or presence of two types of ephrin-A5-Fc intrahippocampal infusion. Microvessels perpendicular to the pyramidal cell layer decreased; however, microvessels that traversed the layer increased, and became distorted and fragmented. The mean densities and diameters of microvessels gradually increased and remained greater than those in the control group at 56 days post-status epilepticus (SE). The upregulation of EphA4 and ephrin-A5 proteins began at 7 days and was maintained until 28 days, subsequently decreasing slightly at 56 days post-SE. Blockade of EphA4 by unclustered-ephrin-A5-Fc effected a reduction in the mean density and mean diameter of microvessels in the CA1 and CA3 areas; conversely, activation of EphA4 by clustered-ephrin-A5-Fc induced an increase in these values. Ephrin-A5 ligand binding to EphA4 receptor may contribute to angiogenesis during epileptogenesis in the hippocampal CA1 and CA3 areas.