Focal injection of the sodium channel blocker tetrodotoxin (TTX) into the injury site at either 5 or 15 min after a standardized thoracic contusion spinal cord injury (SCI) reduces white matter pathology and loss of axons in the first 24 hr after injury. Focal injection of TTX at 15 min after SCI also reduces chronic white matter loss and hindlimb functional deficits. We have now tested the hypothesis that the reduction in chronic deficits with TTX treatment is associated with long-term preservation of axons after SCI and compared both acute (24 hr) and chronic (6 weeks) effects of TTX administered at 15 min prior to and 5 min or 4 hr after SCI. Our results indicate a significant reduction of acute white matter pathology in rats treated with TTX at 15 min before and 5 min after injury but no effect when treatment was delayed until 4 hr after contusion. Compared with injury controls, groups treated with TTX at 5 min and 4 hr after injury did not show a significant deficit reduction, nor was there a significant sparing of white matter at 6 weeks compared with injury controls. In contrast, the group treated with TTX at 15 min before SCI demonstrated significantly reduced hindlimb functional deficits beginning at 1 week after injury and throughout the 6 weeks of the study. This was associated with a significantly higher axon density in the ventromedial white matter at 6 weeks. The results demonstrate that blockade of sodium channels preserves axons from loss after SCI and points to the importance of time of administration of such drugs for therapeutic effectiveness. J. Neurosci. Res. 66:191–202, 2001. © 2001 Wiley-Liss, Inc.