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Cavernous malformations (CMs) are vascular abnormalities with a hemorrhage risk of 0.2% to 5% per year, according to their location. Brainstem CMs seem to have a greater hemorrhagic risk and represent a neurosurgical challenge. We report here the first transsylvian transuncal (TS-TU) approach for an anteromedial mesencephalic CM resection.A 29-yr-old female suddenly presented a left hemiparesis and central facial paresis with a diplopia in the upward gaze. A cerebral imagery revealed an 18-mm right cerebral peduncle CM with signs of acute hemorrhage. Two months later, she rebleed while pregnant. The pregnancy was interrupted. Five months later, a 3.0 Tesla magnetic resonance imaging (MRI) with diffusion tensor imaging sequences was realized for preoperative planning followed by a gross total resection of the CM through a TS-TU approach to avoid the perforating arteries of the anterior perforated substance. The patient presented postoperatively again a left hemiparesis and central facial paresis with a right oculomotor nerve paresis. On the tenth postsurgical day, she developed a Holmes' tremor of the left upper limb, for which a Levodopa treatment was initiated. Three months postoperative, MRI showed a gross total resection of the mesencephalic CM without complications. A complete clinical recovery was observed 1 yr later.We describe here the first performance of a TS-TU approach for an anterior mesencephalic CM resection. This surgical approach allowed direct access to the CM, avoiding the vascularization of the anterior perforated substance.