To evaluate the role of intracranial electroencephalography monitoring in diagnosing and directing the appropriate therapy for MRI‐negative epilepsy and to present the surgical outcomes of patients following treatment.

Retrospective chart review between 2015‐2021 at a single institution identified 48 patients with no lesion on MRI, who received surgical intervention for their epilepsy. The outcomes assessed were the surgical treatment performed and the International League Against Epilepsy seizure outcomes at 1 year of follow‐up.

Eleven patients underwent surgery without invasive monitoring, including vagus nerve stimulation (10%), deep brain stimulation (8%), laser interstitial thermal therapy (2%), and callosotomy (2%). The remaining 37 patients received invasive monitoring followed by resection (35%), responsive neurostimulation (21%), and deep brain stimulation (15%) or no treatment (6%). At 1 year postoperatively, 39% were Class 1‐2, 36% were Class 3‐4 and 24% were Class 5. More patients with Class 1‐2 or 3‐4 outcomes underwent invasive monitoring (100% and 83% respectively) compared with those with poor outcomes (25%, P < .001). Patients with Class 1‐2 outcomes more commonly underwent resection or responsive neurostimulation: 69% and 31%, respectively (P < .001).

The optimal management of MRI‐negative focal epilepsy may involve invasive monitoring followed by resection or responsive neurostimulation in most cases, as these treatments were associated with the best seizure outcomes in our cohort. Unless multifocal onset is clear from the noninvasive evaluation, invasive monitoring is preferred before pursuing deep brain stimulation or vagal nerve stimulation directly.