This study was aimed to investigate whether 4e-binding protein 1 is activated during temporal lobe epileptogenesis. We used the hippocampus of patients with refractory temporal lobe epilepsy (TLE), diagnosed with hippocampal sclerosis (HS) or non-HS, to examine the distribution of phospho-4e-binding protein 1 (p4EBP1) by immunohistochemical staining (n=3-5). We also examined p4EBP1 in the kainic acid (KA)-induced mouse model of TLE before and after anticonvulsant treatment (n=3 per group). The results showed that the hippocampus of both patients with HS and KA mouse model displayed significantly upregulated p4EBP1 immunoreactivity in glial fibrillary acidic protein-positive astrocytes in hippocampus. Quantitative results showed that there is a 5.9-fold upregulation in the number of p4EBP1+glia-like cells in TLE group than control group (P<0.05). However, treatment with lamotrigine failed to suppress spontaneous seizures and did not affect the astrocytic distribution of p4EBP1 (P=0.73). Taken together, we investigated the spatiotemporal expression of p4EBP1 in the sclerotic hippocampus of both patients and a KA-induced mouse model and found glia activation of 4e-binding protein 1 in TLE. Our findings suggest that the upregulation of p4EBP1 in astrocytes may play a critical role in the pathogenesis of TLE.