Objective To explore the correlation between the epilepsy induced by interleukin-2 (IL-2) and changes of NMDA receptor(NMDAR) and estrogen receptor(ER). Methods Methods of immunohistochemistry, double fluorescent immunohistochemistry and laser scanning confocal microscopy were applied to study the expression changes of NMDAR-1 and ER and the coexistence of NMDAR/ER and NMDAR/IL-2R in the brains of rats with epilepsy induced by IL-2 or rats treated with immunosuppressants prior to the inducement. Results The rats displayed an obvious seizure after the lateral ventricle was injected with IL-2. The expressions of NMDAR-1 and ER were markedly increased and there was a significant difference in immunoreactive average absorbance (A) in cerebral cortex and hippocampus between IL-2 group and the control group. However, with the pretreatment of IL-2 inhibitors, such as cyclosporine or glucocorticoid, the epileptic behaviors of rats with IL-2 were inhibited and the immunoreaction of NMDAR-1 and ER was obviously decreased compared with IL-2 group (P<0.05). It was also found that NMDAR/IL-2R or NMDAR/ER coexisted largely in cerebral cortex and hippocampus. Conclusion IL-2 could induce epilepsy. There exist cooperation and interaction between NMDAR-1, IL-2R and ER in epileptogenic mechanisms.