Acute spinal cord injury (SCI) produces tissue damage that continues to evolve days and weeks after the initial insult, with corresponding functional impairments. Reducing the extent of progressive tissue loss ('neuroprotection') following SCI should result in a better recovery from SCI, but treatment options have thus far been limited. In this study, we have tested the efficacy of minocycline in ameliorating damage following acute SCI in mice. This semi-synthetic tetracycline antibiotic has been reported to inhibit the expression and activity of several mediators of tissue injury, including inflammatory cytokines, free radicals and matrix metalloproteinases, making it a suitable candidate for study. Mice were subjected to extradural compression of the spinal cord using a modified aneurysm clip, following which they received treatment with either minocycline or vehicle beginning 1 h after injury. Behavioural testing of hindlimb function was initiated 3 days after injury using the Basso Beattie Bresnahan locomotor rating scale, and at 1 week using the inclined plane test. Functional assessments demonstrated that minocycline administration significantly improved both hindlimb function and strength from 3 to 28 days after injury compared with vehicle controls. Furthermore, gross lesion size in the spinal cord was significantly reduced by minocycline, and there was evidence of axonal sparing as determined using fluorogold labelling of the rubrospinal tract and by Bielchowsky silver stain. Finally, a comparison of minocycline against the currently approved treatment for acute SCI in humans, methylprednisolone, demonstrated superior behavioural recovery in the minocycline-treated animals.