Transient focal lesions in the splenium of the corpus callosum (SCC) have been associated with antiepileptic drug (AED) treatment. However, the aetiology is widely unknown. We describe a transient SCC lesion in an epilepsy patient after abrupt AED reduction. Whole head high-field diffusion tensor imaging (DTI) including fully automated quantitative fractional anisotropy (FA) analysis was used to get insight into the pathophysiology of transient SCC lesions. Our results demonstrate that a reversible loss of directional fibre organisation in the splenium, likely due to intramyelinic oedema, is the morphological correlate of transient SCC lesions. We conclude that DTI provides a highly sensitive and quantitative tool to detect subtle and transient loss of fibre integrity associated with AED treatment.