To test the hypothesis that macrophage migration inhibitory factor (MIF) is elevated in the circulation of individuals with acute spinal cord injury (SCI) compared with uninjured individuals. Prospective, observational pilot study. Academic medical center. Adults with acute traumatic SCI (n=18) and uninjured participants (n=18), comparable in age and sex distribution. Not applicable. The primary outcome measure was the plasma MIF levels. Potential correlations were examined between MIF and clinical/demographic variables. The secondary outcome was to determine if other immune mediators were elevated in participants with acute SCI and if their levels correlated with the MIF. MIF was significantly elevated in subjects with acute SCI compared with control subjects at 0 to 3 (P<.0029), 4 to 7 (P<.0001), and 8 to 11 (P<.0015) days postinjury (DPI). At 0 to 3 DPI, levels of cytokines interleukin-6 (P<.00017), interleukin-9 (P<.0047), interleukin-16 (P<.007), interleukin-18 (P<.014), chemokines growth-related oncogene α/chemokine (C-X-C motif) ligand 1 (P<.0127) and macrophage inflammatory protein 1-β/chemokine (C-C motif) ligand 4 (P<.0015), and growth factors hepatocyte growth factor (HGF) (P<.0001) and stem cell growth factor-β (P<.0103) were also significantly elevated in subjects with acute SCI. With the exception of interleukin-9, all of these factors remained significantly elevated at 4 to 7 DPI; a subset (interleukin-16, HGF, stem cell growth factor-β) remained elevated throughout the study. Within individuals, MIF levels correlated with HGF (P<.018) and interleukin-16 (P<.01). These data demonstrate that MIF is significantly elevated in subjects with acute SCI, supporting further investigation of MIF and other inflammatory mediators in acute SCI, where they may contribute to primary and secondary functional outcomes.