INTRODUCTION: Considerable connections between migraine with aura and cortical spreading depression (CSD), a depolarization wave originating in the visual cortex and traveling toward the frontal lobe, lead to the hypothesis that CSD is underlying migraine aura. The highly individual and complex characteristics of the brain cortex suggest that the geometry might impact the propagation of cortical spreading depression. METHODS: In a single-case study, we simulated the CSD propagation for five migraine with aura patients, matching their symptoms during a migraine attack to the CSD wavefront propagation. This CSD wavefront was simulated on a patient-specific triangulated cortical mesh obtained from individual MRI imaging and personalized diffusivity tensors derived locally from diffusion tensor imaging data. RESULTS: The CSD wave propagation was simulated on both hemispheres, despite in all but one patient the symptoms were attributable to one hemisphere. The CSD wave diffused with a large wavefront toward somatosensory and prefrontal regions, devoted to pain processing. DISCUSSION: This case-control study suggests that the cortical geometry may contribute to the modality of CSD evolution and partly to clinical expression of aura symptoms. The simulated CSD is a large and diffuse phenomenon, possibly capable to activate trigeminal nociceptors and to involve cortical areas devoted to pain processing.