Glucocorticoids (GCs) are effective anti-inflammatory agents widely used in therapeutic approach to treatment of spinal cord trauma. Previous results suggest that peroxisome proliferator activated receptor alpha (PPAR-alpha), an intracellular transcription factor activated by fatty acids, plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI). With the aim to characterize the role of PPAR-alpha in GC-mediated anti-inflammatory activity, we tested the efficacy of dexamethasone (DEX), a synthetic GC specific for glucocorticoid receptor (GR), in an experimental model of spinal cord trauma induced in mice by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-alpha (PPAR-alphaKO) with wild type (WT) mice. Results indicate that DEX-mediated anti-inflammatory activity is weakened in PPAR-alphaKO mice, as compared to WT controls. In particular, DEX was less effective in PPAR-alphaKO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation and tissue injury, neutrophil infiltration, nitrotyrosine formation, pro-inflammatory cytokine expression, NF-kappaB activation, inducible nitric-oxide synthase (iNOS) expression; and apoptosis. This study indicates that PPAR-alpha can contribute to the anti-inflammatory activity of GCs in SCI.