Objective: In children, vitamin B6 (pyridoxine) deficiency has been described as a cause of seizures that are refractory to conventional antiepileptic medications. We describe the clinical presentation of 3 adults with refractory seizures (later diagnosed with vitamin B6 deficiency) that resolved after pyridoxine treatment. Design: Case series. Setting: Tertiary care surgical intensive care unit. Patients: In the first case, a 54-year-old male with history of alcoholic cirrhosis developed new-onset seizures refractory to phenytoin and levetiracetam 8 days after liver transplantation. In the second case, a 59-year-old male with hepatitis C infection developed intracranial hemorrhage and new-onset seizures refractory to phenytoin, levetiracetam, and pentobarbital. The third patient is a 78-year-old male with a history of alcohol dependence who was admitted for an intraventricular bleed and developed new onset of refractory seizures. Interventions: Intravenous pyridoxine followed by oral pyridoxine. Measurement and Main Results: In all 3 cases, seizures persisted despite escalation of conventional antiepileptic medications but resolved within 2 days of pyridoxine supplementation. In each case, low serum pyridoxal 5′-phosphate concentrations normalized with pyridoxine administration. Conclusions: Although refractory seizures caused by vitamin B6 deficiency are rare in adults, it should be considered in critically ill adult patients with refractory seizures.