Background: The precise role of innate immune responses in the early stage of traumatic spinal cord injury (SCI), especially those mediated by natural killer (NK) cells, is poorly understood. Methods: The frequency and phenotype of NK cells from traumatic SCI patients and healthy controls were assessed by flow cytometry. ELISA assay was used to detect the production of a series of cytokines, neurotrophins, and neurohormones in plasma samples. In vitro cell culture was performed to observe brain-derived neurotrophic factor (BDNF)-induced NK cell activation. Results: A significant increase in the NK cell frequency and the presence of NK cells with the activated phenotype was observed, as reflected by the enhanced expression of CD69, HLA-DR, NKG2D, and NKp30 on the NK cells, in traumatic SCI patients within 24 h of injury, compared to case for the healthy controls. Meanwhile, a higher level of BDNF, a member of the neurotrophin family, was observed in the plasma samples of the SCI patients; the elevated level of BDNF was strongly and positively correlated with the percentage of NK cells during the early stage of traumatic SCI. Furthermore, the expression of CD69 and NKp30 on the NK cells increased following stimulation with BDNF for 24 h in vitro, which is consistent with the in vivo observation in SCI patients. Conclusion: Collectively, our findings demonstrate the activation of NK cells within 24 h after traumatic SCI, and reveal a novel role of BDNF in regulating NK cell activation. Keywords: Activation; BDNF; NK cells; Spinal cord injury.