Juvenile myoclonic epilepsy (JME) is often exquisitely responsive to treatment with valproic acid (VPA). However, a subset of patients does not respond to this medication and often has intractable seizures. We wanted to identify differences between these two subsets of JME patients. Charts of all JME patients followed at the Duke Epilepsy Center were reviewed. Clinical parameters, electroencephalogram (EEG) findings and magnetic resonance imaging (MRI) data were reviewed. These features were compared between patients with VPA sensitive and VPA resistant JME. Thirty-three patients with JME were identified: 23 (70%) were VPA sensitive (13 females, 10 males; mean age of onset 15.9 years) and 10 (30%) were VPA resistant (5 females, 5 males; mean age of onset 14.1 years). The VPA resistant group had a higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). Clinical characteristics combined with EEG data may help in predicting which JME patients will respond favorably to VPA. This study also raises the issue whether VPA resistant JME is in fact a localization-related epilepsy.