Objective:The aim of the study was to evaluate the parameters for localizing the seizure onset zone in refractory epilepsy patients using cortico-cortical evoked potentials (CCEP). Methods: Fifteen patients (nine females) with medically refractory partial epilepsy underwent stereo electro encephalography (SEEG) in Tsinghua University Yu-Quan Hospital from 2015 to 2016. Clinical semiology and, scalp electroencephalography (EEG) findings were analyzed during phase I preoperative evaluation. During phase II evaluation, localization of seizure onset zone (SOZ) was analyzed using SEEG by experienced epileptologists. Meanwhile, the cortico-cortical evoked potential (CCEP) paradigm was tested in all patients in phase II. The value of root-mean-square (RMS) of CCEPs amplitude from 7 ms to 300 ms after stimulation was analyzed to quantify the response. Results: RMS of CCEPs amplitude in SOZ was higher than in seizure propagation zone (SPZ) (P < 0.05) and non-seizure onset zone (NSOZ) (P < 0.05). RMS of CCEPs amplitude in SOZ was higher than in NSOZ in epilepsy patients with secondary generalized tonic-clonic seizures (SGTCS) (N = 6, P < 0.05); The RMS of CCEPs amplitude in SOZ was strikingly higher than SPZ in the repetitive spiking (RS) onset pattern, and the difference was significant (N = 5, P < 0.01). Conclusions: This data indicated that CCEP response is enhanced in SOZ despite different seizure types (with or without SGTCS). CCEP may be an effective method to locate SOZ.