We report the case of a 59-year-old male patient suffering from locked-in syndrome (LIS) following basilar artery thrombosis despite an attempt of thrombolysis. Neurological examination showed quadriplegia and aphonia and a state of coma requiring mechanical ventilation was diagnosed. The use of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) allowed to detect a normal 18F-FDG uptake in the main cerebral cortical areas and a significant reduction of 18F-FDG uptake in both cerebellar hemispheres, compatible with a functional deafferentation, helping confirming the clinical suspicion of LIS. The diagnosis of LIS, according to literature, is based on the clinical assessment and the utilization of scores as the Coma Recovery Scale-Revised. The standard neuroimaging techniques, although recognize the site of injury, are not able to differentiate the different conditions affecting a state of altered consciousness. Performing 18F-FDG-PET in patients with LIS might help addressing the correct diagnosis and prompting subsequent appropriate treatment, and therefore, ultimately improving the patient outcome. Therefore, 18F-FDG-PET should be taken into account in the early clinical assessment of doubtful cases.