PURPOSE To assess the safety, tolerability and efficacy of high-frequency periodic thalamic stimulation in inoperable mesial temporal epilepsy and the usefulness of intracranially evoked responses for assessment of anatomical uniformity of lead placement. METHODS Four subjects were implanted with leads aimed at the anterior thalamic nuclei. Six weeks later, Soletra IPGs were activated using parameters similar to the closed-loop trial's (mean: 175 Hz; 4.1 V; 90 mus; 1 min ON, 5 min OFF). Efficacy was assessed by comparing percentage change in seizure frequency over a 6-month baseline versus a 36-month treatment period, using a within-subjects repeated measures design. Tolerability and safety were similarly monitored. Evoked responses elicited by thalamic stimulation were recorded from depth electrodes in the amygdalo-hippocampal regions and compared intra and interindividually. RESULTS All subjects completed the study, tolerated stimulation and had no serious adverse effects. Mean reduction in seizure frequency was 75.6% (t =-8.24; p < or = 0.01) (range: 92% to 53%). Quality of life improved in all. Verification of electrode placement with a software function indicated that stimulated structures were presumably, Anterior thalami, Latero-polaris, Reticulatus Polaris, Ventro-oralis Internus, and Campus Forelii. Evoked responses from stimulated sites were heterogeneous, intra and interindividually, also suggesting a lack of uniformity in lead placement. CONCLUSIONS High-frequency, periodic, round-the-clock thalamic stimulation seems safe, well tolerated and efficacious for inoperable mesial temporal epilepsy. Identification of clinically useful parameters may be facilitated by brief closed-loop trials. Selective stimulation of a single structure may not be feasible at certain intensities, nor required for efficacy. Evoked responses may be useful for verification of uniformity of target acquisition.