Temporal lobe epilepsy (TLE) is a frequent form of focal intractable epilepsy in adults, but the specific mechanism underlying the epileptogenesis of TLE is still unknown. Human leukocyte immunoglobulin-like receptor B2 (LILRB2) (the murine homolog gene called paired immunoglobulin-like receptor B, or PirB), participates in the process of synaptic plasticity and neurite growth in the central nervous system (CNS), suggesting a potential role of LILRB2 in epilepsy. However, the expression pattern of LILRB2 and the downstream molecular signal in intractable TLE remains poorly understood. In the present study, western blotting and immunohistochemistry results showed that LILRB2 expression was upregulated in the temporal neocortex of patients with TLE. Moreover, protein levels of LILRB2 negatively correlated with the frequency of seizures in TLE patients. In the pilocarpine-induced C57BL/6 mouse model, PirB upregulation in the hippocampus began 12 h after status epilepticus (SE), reached a peak at 7 days and then maintained a significantly high level until day 60. Similarly, we found a remarkable increase in PirB expression at 1 day, 7 days and30days post-SE in the temporal cortex. Double-labeled immunofluorescence showed that LILRB2/PirB were highly expressed in neurons and astrocytes but not microglia. In addition, protein levels of POSH, SHROOM3, ROCK1 and ROCK2, the important downstream factors of the LILRB2 pathway, were significantly increased in the epileptic foci of TLE patients and located on the NeuN-positive neurons and GFAP-positive astrocytes. Taken together, our results indicate that LILRB2/PirB may be involved in the process of TLE.