Purpose: Concerns about the impact of open surgery for drug-resistant mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) have driven interest in minimally invasive techniques. Stereo-electro-encephalography guided radiofrequency thermocoagulation (SEEG guided RF-TC) offers an alternative choice but with currently limited efficacy. We developed a procedure for optimally extended thermocoagulative lesions and investigated the efficacy and safety for MTLE-HS in a preliminary observational study. Methods: From June 2016 to August 2017, twenty-two patients were selected for the present study. They met the criteria of unilateral MTLE-HS after noninvasive evaluation and then underwent implantation of a combination of SEEG electrodes to form a high-density focal stereo-array, including one electrode along the long axis of amygdalohippocampal complex and three orthogonal electrodes to widely sample mesial temporal structures. A unilateral epileptogenic zone of mesial temporal structures was confirmed in these 21 patients. SEEG-guided bipolar coagulations were performed between two contiguous contacts of the same electrode, or between two adjacent contacts of different electrodes. Results: Surgical procedures were well tolerated, with no related complications. At the follow-up of 12 months, 20 patients (95.2%) experienced a >90% decrease in seizure frequency and 16 patients (76.2%) were free of disabling seizures (Engel class I). Among them, eight (38.1%) were classified as Engel class Ia and the other eight (38.1%) as Engel class Ib. Four others (19%) had rare disabling seizures (Engel class II). Only one (4.8%) experienced an Engel class III outcome. Conclusion: Optimized SEEG-guided RF-TC is a promising complementary option for the treatment of MTLE-HS. © 2019