Spinal cord injury (SCI) involves the loss of neurons and glia due to initial mechanical and secondary biochemical mechanisms. Treatment with the sodium channel blocker tetrodotoxin (TTX) reduces acute white matter pathology and increases both axon density and hindlimb function chronically at 6 weeks after injury. We investigated the cellular composition of residual white matter chronically to determine whether TTX also has a significant effect on the numbers and types of cells present. Rats received an incomplete thoracic contusion injury, in the presence or absence of TTX (0.15 nmole) injected focally, beginning at 15 min prior to injury. Six weeks later, cell density was significantly increased in the residual white matter of the dorsal, lateral, and ventral funiculi, both rostral and caudal to the injury site in both TTX-treated and injury control groups. Oligodendrocyte and astrocyte density was similar to normal but large numbers of cells expressing microglia/macrophage markers were present. Labeling with the progenitor markers nestin and NG2 showed that precursor cell density had also doubled or tripled as compared with uninjured controls. Some of these cells were also labeled for antigens that indicate their possible progression along an oligodendrocyte or astrocyte lineage. Our results support the hypothesis that the beneficial effect of TTX in SCI is related to its preservation of axons per se; no effect on chronic white matter cell composition was detected. They highlight the profound changes in cellular composition in preserved white matter chronically at 6 weeks after injury, including the accumulation of endogenous progenitor cells and the persistence of activated macrophages/microglia. The manipulation of these endogenous cells may be used in the future to enhance recovery after SCI. © 2004 Wiley-Liss, Inc.