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Background Spinal cord ischemia (SCI) remains a devastating complication after aortic dissection or repair. A primary hypoxic damage is followed by a secondary damage resulting in further cellular loss via apoptosis. Affected patients have a poor prognosis and limited therapeutic options. Shock wave therapy (SWT) improves functional outcome, neuronal degeneration and survival in murine spinal cord injury. In this first‐in‐human study we treated 5 patients with spinal cord ischemia with SWT aiming to prove safety and feasibility. Methods and Results Human neurons were subjected to ischemic injury with subsequent SWT. Reactive oxygen species and cellular apoptosis were quantified using flow cytometry. Signaling of the antioxidative transcription factor NRF2 (nuclear factor erythroid 2‐related factor 2) and immune receptor Toll‐like receptor 3 (TLR3) were analyzed. To assess whether SWT act via a conserved mechanism, transgenic tlr3−/− zebrafish created via CRISPR/Cas9 were subjected to spinal cord injury. To translate our findings into a clinical setting, 5 patients with SCI underwent SWT. Baseline analysis and follow‐up (6 months) included assessment of American Spinal Cord Injury Association (ASIA) impairment scale, evaluation of Spinal Cord Independence Measure score and World Health Organization Quality of Life questionnaire. SWT reduced the number of reactive oxygen species positive cells and apoptosis upon ischemia via induction of the antioxidative factor nuclear factor erythroid 2‐related factor 2. Inhibition or deletion of tlr3 impaired axonal growth after spinal cord lesion in zebrafish, whereas tlr3 stimulation enhanced spinal regeneration. In a first‐in‐human study, we treated 5 patients with SCI using SWT (mean age, 65.3 years). Four patients presented with acute aortic dissection (80%), 2 of them exhibited preoperative neurological symptoms (40%). Impairment was ASIA A in 1 patient (20%), ASIA B in 3 patients (60%), and ASIA D in 1 patient (20%) at baseline. At follow‐up, 2 patients were graded as ASIA A (40%) and 3 patients as ASIA B (60%). Spinal cord independence measure score showed significant improvement. Examination of World Health Organization Quality of Life questionnaires revealed increased scores at follow‐up. Conclusions SWT reduces oxidative damage upon SCI via immune receptor TLR3. The first‐in‐human application proved safety and feasibility in patients with SCI. SWT could therefore become a powerful regenerative treatment option for this devastating injury.