Background: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an emerging form of adjunctive therapy in focal refractory epilepsy. Unlike conventional DBS targets, the ANT is both encapsulated by white matter layers and located immediately adjacent to the cerebrospinal fluid (CSF) space. Owing to the location of the ANT, implantation has most commonly been performed using a transventricular trajectory. Previous studies suggest different electrical conductivity between gray matter, white matter, and CSF. Objectives: In this study, we asked whether therapeutic impedance values from a fully implanted DBS device could be used to deduce the actual location of the active contact to optimize the stimulation site. Secondly, we tested whether impedance values correlate with patient outcomes. Materials and Methods: A total of 16 patients with ANT-DBS for refractory epilepsy were evaluated in this prospective study. Therapeutic impedance values were recorded on regular outpatient clinic visits. Contact locations were analyzed using delayed contrast-enhanced postoperative computed tomography–3T magnetic resonance imaging short tau inversion recovery fusion images previously shown to demonstrate anatomical details around the ANT. Results: Transventricularly implanted contacts immediately below the CSF surface showed overall lower and slightly decreasing impedances over time compared with higher and more stable impedances in contacts with deeper parenchymal location. Impedance values in transventricularly implanted contacts in the ANT were significantly lower than those in transventricularly implanted contacts outside the ANT or extraventricularly implanted contacts that were typically at the posterior/inferior/lateral border of the ANT. Increasing contact distance from the CSF surface was associated with a linear increase in therapeutic impedance. We also found that therapeutic impedance values were significantly lower in contacts with favorable therapy response than in nonresponding contacts. Finally, we observed a significant correlation between the left- and right-side averaged impedance and the reduction of the total number of seizures. Conclusions: Valuable information can be obtained from the noninvasive measurement of therapeutic impedances. The selection of active contacts to target stimulation to the anterior nucleus may be guided by therapeutic impedance measurements to optimize outcome.