SummaryObjectiveStereo electroencephalography (SEEG)–guided radiofrequency thermocoagulation (SEEG‐guided RF‐TC) has been proposed since 2004 as a possible treatment of some focal drug‐resistant epilepsy. The aim of this study is to provide extensive data about efficacy and safety of SEEG‐guided RF‐TC.MethodsOver a 10‐year period, 162 patients with drug‐resistant focal epilepsy were eligible for SEEG‐guided RF‐TG during phase II invasive investigation by SEEG. All follow‐up and safety data were collected prospectively. The primary outcome was seizure freedom at 2 months and at 1 year after SEEG‐guided RF‐TC. Secondary outcomes were the responders' rate (patient with at least 50% decrease in seizure frequency) and their long‐term follow‐up.ResultsTwenty‐five percent of patients were seizure‐free at 2 months and 7% at 1 year. We reported 67% of responders at 2 months and 48% at 1 year; 58% of responders maintained their status during the long‐term follow‐up. The seizure outcome was significantly better when the SEEG‐guided RF‐TC involved the occipital region (p = 0.007). When surgery followed an SEEG‐guided RF‐TC, the positive predictive value of being a responder 2 months after an SEEG‐guided RF‐TC and to be Engel's class I or II after surgery was 93%. We reported 1.1% of permanent deficit and 2.4% of transient side effects.SignificanceOur results, gathered in a large population over a 10‐year period, confirm that SEEG‐guided RF‐TC is a safe technique, being efficient in many cases. More than two thirds of patients showed a short‐term improvement, and almost half of them were responders at 1‐year follow‐up. The technique appears to be especially interesting for limited epileptic zone inaccessible to surgery and when epilepsy is related to a large unilateral network (network disruption by multiple RF‐TC). Furthermore, SEEG‐guided RF‐TC effect is a predictor of outcome after conventional cortectomy in patients eligible for surgery.