Objective The purpose of this study was to explore the expressions of EPO-R, JAK2 and STAT-5 in the human brain with refractory epilepsy and the role in neural apotosis. Methods Collecting the brain tissue of 24 patients with intractable epilepsy (as experimental group) who were hospitalized and underwent surgery in the Epilepsy Center of the First Hospital Jilin University between March 2010 to July 2011 and 6 cases of accidental or unnatural death immediately following autopsy (as control group) as required by law during the same term. Immunohistochemical was performed to observe the expression of EPO-R, JAK2 and STAT-5 in brain tissue and statistical analysis was performed. Results ① EPO-R, JAK2 and STAT-5 were expressed in both experimental and control groups. In experimental group, the positive-cell number were 41.05±2.40, 50.21±2.50 and 60.18±2.84 under light microscope (400×). While in control group, the positive-cell number were 23.00±0.49, 27.00±0.88 and 25.93±0.33. There were significant differences between the 2 groups (P<0.001). ② There were the pathologic and ultrastructural changes in the human brain with refractory epilepsy. Under the optical microscope, we can observe that the distribution of neurons was uneven and immature neurons were visible. We can see that the nuclei were vacuolar, less cytoplasm, dark staining, hyalomitome acidophilic body, and the neurons became triangular due to degeneration. The proliferation and hyperemia appeared in small vascular and glial cells. Under the transmission electron microscope we observed degeneration and necrosis of the nerve cells, nuclear karyopyknosis, nucleolis dyssymmetry and karyolemma breakage and even dissolution. The mitochondria and astrocytes were swelling. We also saw that part of the mitochondrial cristae was abnormal. Conclusion ① We found neuronal apotosis in the human brain with refractory epilepsy. ② The expression of EPO-R, JAK2 and STAT-5 in intractable epilepsy was significantly increased in neurons and glial cells compared with the control group. The high expression of EPO-R, JAK2 and STAT-5 is unrelated with course and frequency of epileptic seizures. ③ The pathway of EPO-R/JAK2/STAT-5 may be involved in the pathophysiological processes of neural protective effect of endogenous EPO against brain injury induced by epileptic seizures.