INTRODUCTION: Responsive neurostimulation (RNS) is an FDA-approved therapy for focal drug-resistant epilepsy (DRE). Emerging evidence supports a role for RNS in DRE with regional, multifocal, or non-resectable seizure onset zones. The centromedian nucleus of the thalamus (CMT) is a promising target, although descriptions of predictors of longer-term response are lacking. METHODS: We retrospectively reviewed patients who underwent RNS implantation with at least one CMT electrode at Baylor College of Medicine (BCM) and the University of Utah (UoU) from 2019-2023. Patients with = 6 months of follow-up were assessed for changes in clinical seizure frequency following surgery, as well as changes in seizure severity and subjective quality-of-life (QoL). RESULTS: Sixteen patients underwent CMT RNS (n = 12 BCM, n = 4 UoU) at a median age of 30 years [range 20-51] with a median 19-year history of epilepsy. All patients were evaluated by a multidisciplinary team that recommended thalamic RNS. Thirteen underwent bilateral CMT implantation and 7 had a documented lesional effect (>50% reduction in seizures in the months following implantation). Thirteen patients had = 6-month follow-up with which to do subsequent seizure outcome analysis. In these patients, with a median follow-up of 18 months [6-40], median clinical seizure reduction was 80% [0-100%], 2 patients were seizure free for 6 months, and 1 was seizure free for 40 months. Patients with a lesional effect had a median 87% seizure reduction at last follow-up while those without a lesional effect had a 51% seizure reduction (two-tailed, two-sample t-test, p = 0.04). Subjective reduced seizure severity and increased QoL was documented in 92% of patients. CONCLUSIONS: RNS of the CMT can result in robust seizure frequency, severity, and QoL improvements in patients with DRE. Post-implantation lesional effect may be associated with longer-term improved response.