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Spinal cord injury (SCI) leads to complex secondary events that expand and exacerbate the injury. Methylprednisolone (MP) has been considered a standard of care for acute SCI. The purpose of this study was to test the effects of MP, in severe and more moderate severe clip-compression models of SCI, on the measures of neurological function and lesion sparing that we used previously to assess a highly effective anti-inflammatory therapy, a monoclonal antibody (mAb) to the CD11d integrin. Intravenous treatment with the anti-CD11d mAb blocks the infiltration of leukocytes into the lesion, limits secondary cord damage, and improves neurological outcomes. We also undertook a 2- week study of effects of these two therapies in combination. To permit direct comparison, the new findings with MP are presented together with reference to the previously published effects of the mAb. The severe SCI was at the 4(th) thoracic segment (T4), causing extensive motor dysfunction; the more moderate SCI was at T12 and caused less locomotor loss but the induction of mechanical allodynia. Neither MP alone nor the combination treatment improved Basso, Beattie, and Bresnahan 21-point open-field locomotor scores at 2-12 weeks after SCI. These scores were ~4 points in the control, MP, and combination treatment groups, respectively, at 2 weeks after severe SCI at T4. By 6 weeks after T4 SCI, scores in the control and MP groups were ~7. At 12 weeks after the more moderate T12 injury, scores were ~8 in both control and MP treatment groups. MP treatment had no consistent effect on mechanical allodynia during 12 weeks after SCI. Control and MP-treated rats responded to approximately five of 10 stimuli to their backs and three of 10 stimuli to their hind paws. MP treatment increased areas of neurofilament and myelin near the injury site at T4 and T12. Thus, MP treatment spared tissue, but had no corresponding effect on neurological function. In contrast, the combination treatment did not spare myelin significantly. These neurological outcomes after treatment with MP contrast with the consistent and significant improvements after treatment with the anti-CD11d mAb. Effects of MP on the lesion were significant, but myelin sparing was less than that caused by the anti-CD11d mAb. The presence of MP in the combination therapy appeared to reverse the positive effects of the mAb. The poor neurological outcome after MP treatment may relate to the long-lasting reduction in hematogenous monocyte/macrophages within the injury site that it causes and to the prolongation of a neutrophil presence. These findings demonstrate that the non-selective and enduring effects of immunosuppressive therapy with MP not only fail to improve neurological outcomes, but also can block the beneficial actions of selective therapies such as the anti-CD11d mAb. Combination treatments that cause intense immunosuppression should be viewed with caution.