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Summary Background Approximately 20% of traumatic cervical spinal cord injuries result in tetraplegia. Neuroprosthetics are being developed to manage this condition and thus improve the lives of patients. We aimed to test the feasibility of a semi-invasive technique that uses brain signals to drive an exoskeleton. Methods We recruited two participants at Clinatec research centre, associated with Grenoble University Hospital, Grenoble, France, into our ongoing clinical trial. Inclusion criteria were age 18–45 years, stability of neurological deficits, a need for additional mobility expressed by the patient, ambulatory or hospitalised monitoring, registration in the French social security system, and signed informed consent. The exclusion criteria were previous brain surgery, anticoagulant treatments, neuropsychological sequelae, depression, substance dependence or misuse, and contraindications to magnetoencephalography (MEG), EEG, or MRI. One participant was excluded because of a technical problem with the implants. The remaining participant was a 28-year-old man, who had tetraplegia following a C4–C5 spinal cord injury. Two bilateral wireless epidural recorders, each with 64 electrodes, were implanted over the upper limb sensorimotor areas of the brain. Epidural electrocorticographic (ECoG) signals were processed online by an adaptive decoding algorithm to send commands to effectors (virtual avatar or exoskeleton). Throughout the 24 months of the study, the patient did various mental tasks to progressively increase the number of degrees of freedom. Findings Between June 12, 2017, and July 21, 2019, the patient cortically controlled a programme that simulated walking and made bimanual, multi-joint, upper-limb movements with eight degrees of freedom during various reach-and-touch tasks and wrist rotations, using a virtual avatar at home (64·0% [SD 5·1] success) or an exoskeleton in the laboratory (70·9% [11·6] success). Compared with microelectrodes, epidural ECoG is semi-invasive and has similar efficiency. The decoding models were reusable for up to approximately 7 weeks without recalibration. Interpretation These results showed long-term (24-month) activation of a four-limb neuroprosthetic exoskeleton by a complete brain–machine interface system using continuous, online epidural ECoG to decode brain activity in a tetraplegic patient. Up to eight degrees of freedom could be simultaneously controlled using a unique model, which was reusable without recalibration for up to about 7 weeks. Funding French Atomic Energy Commission, French Ministry of Health, Edmond J Safra Philanthropic Foundation, Fondation Motrice, Fondation Nanosciences, Institut Carnot, Fonds de Dotation Clinatec.