Objectives: Patients with tuberous sclerosis complex (TSC) present multiple cortical tubers in the brain, which are responsible for epilepsy. It is still difficult to localize the epileptogenic tuber. The value of cortico-cortical evoked potentials (CCEPs) was assessed in epileptogenic tuber localization in patients with TSC using stereo-electroencephalography (SEEG). Methods: Patients with TSC who underwent SEEG and CCEP examination in preoperative evaluation during 2014-2017 and reached postoperative seizure freedom at 1-year follow-up were enrolled in this study (n = 11). CCEPs were conducted by stimulating every two adjacent contacts of SEEG electrodes and recording on other contacts of SEEG electrodes in one epileptogenic tuber and its early-stage propagating tuber, and their perituberal cortexes in each patient. The CCEP was defined as positive when N1 and/or N2 wave presented, and then the occurrence rates of positive CCEPs were then compared among different tubers and perituberal regions. Results: Occurrence rates of positive CCEP from epileptogenic tubers to early propagating tubers and epileptogenic tubers to perituberal cortexes were 100%, which were significantly higher than the occurrence rates of CCEP between other locations. The occurrence rates of CCEP from peripheral portions of epileptogenic tubers to peripheral portions of early propagating tubers or perituberal cortexes were 100%, which were significant higher than the occurrence rates of CCEP from peripheral regions of early propagating tubers to peripheral portions of epileptogenic tubers, from the central part of early propagating tuber to central portions of epileptogenic tubers, or from perituberal cortexes to the center part of epileptogenic tubers. Conclusion: Epileptogenic tubers presented much more diffusive connectivity with other tubers and perituberal cortexes than any other connectivity relationships across propagating tubers, and the peripheral region of epileptogenic tubers presented the greatest connectivity with propagating tubers and perituberal cortexes. CCEP can be an effective tool in epileptogenic tuber localization in patients with TSC.