Many adults with epilepsy have breakthrough seizures despite treatment with antiepileptic drugs (AEDs), requiring them to have a rescue medication as part of a comprehensive treatment plan. We evaluated the effectiveness and tolerability of rectal diazepam in the treatment of breakthrough seizures in adult patients with epilepsy. We identified 50 such patients who had used diazepam rectal gel for clusters of seizures defined as acute repetitive seizures, prolonged seizures, or both, in the previous 18 months. Information on diagnoses, dose, frequency of use, reasons for use, safety, and efficacy was collected. Diazepam rectal gel was effective in stopping seizures in 45 patients (90%). Somnolence was reported in most patients, but no other adverse events were reported. Diazepam rectal gel demonstrates efficacy and tolerability as a seizure rescue medication for adult patients with a variety of seizure types, and may help improve quality of life.