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5 reviewsA spinal cord injury (SCI) causes immediate and sustained hemodynamic Check for updatesinstability that threatens neurological recovery and impacts quality of life. Here we establish the clinical burden of chronic hypotensive complications due to SCI in 1,479 participants and expose the inefective treatment of these complications with conservative measures. To address this clinical burden, we developed a purpose-built implantable system based on biomimetic epidural electrical stimulation (EES) of the spinal cord that immediately triggered robust pressor responses. The system durably reduced the severity of hypotensive complications in people with SCI, removed the necessity for conservative treatments, improved quality of life and enabled superior engagement in activities of daily living. Central to the development of this therapy was the head-to-head demonstration in the same participants that EES must target the last three thoracic segments, and not the lumbosacral segments, to achieve the safe and efective regulation of blood pressure in people with SCI. These fndings in 14 participants establish the path to designing a pivotal device trial that will evaluate the safety and efcacy of EES to treat the underappreciated, treatment-resistant hypotensive complications due to SCI.