Summary Purpose Up to 30% of patients with idiopathic generalized epilepsy (IGE) have seizures that are refractory to medication despite appropriate therapy that commonly includes valproate (VPA). The aim of this study was to compare patients with VPA-refractory and VPA-responsive IGE in order to determine whether there are group differences in generalized spike and wave discharge (GSWD) generators that may be associated with VPA resistance. Methods Of 89 IGE patients who underwent electroencephalography (EEG) combined with functional magnetic resonance imaging (fMRI; EEG/fMRI), 25 with GSWDs identified in EEG/fMRI data were included. Simultaneous acquisition of 64 channels of EEG data at 10 kHz was performed using an MRI-compatible EEG cap and amplifier at 4T. VPA resistance was defined as lack of seizure control despite therapeutic dose of VPA. Key Findings The fMRI blood oxygen-level dependent (BOLD) correlates of GSWD in the entire group involved midline thalamus, frontal regions comprising Brodmann areas 6, 24, and 32, and temporal lobes diffusely. When VPA-responsive and VPA-resistant patients were compared, BOLD signal increases were noted in the VPA-resistant patients in medial frontal cortex, along the paracingulate gyrus (Montreal Neurological Institute; MNI x = 2, y = 13.6, z = 45.9), and anterior insula bilaterally (right MNI x = 37.6, y = 7.8, z = 0.6, left MNI x = -35.3, y = 13.6, z = -5.3). Significance Our findings support the hypothesis that VPA-resistant and VPA-responsive patients may have different GSWD generators. Furthermore, we hypothesize that these differences in GSWD generators may be the reason for different responses to VPA. © Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.