After an incomplete spinal cord injury (SCI), partial recovery of locomotion is accomplished with time. Previous studies have established a functional link between extension of axon collaterals from spared spinal tracts and locomotor recovery after SCI, but the tissular signals triggering collateral sprouting have not been identified. Here, we investigated whether axonal degeneration after SCI contributes to the sprouting of collaterals from axons spared after injury. To this end, we evaluated collateral sprouting from BOA-labeled uninjured corticospinal axons after spinal cord hemisection (SCIH) in wild type (WT) mouse and Wld(s) mouse strains, which shows a significant delay in Wallerian degeneration after injury. After SCIH, spared fibers of WT mice extend collateral sprouts to both intact and denervated sides of the spinal cord distant from the injury site. On the contrary, in the Wlds mice collateral sprouting from spared fibers was greatly reduced after SCIH. Consistent with a role for collateral sprouting in functional recovery after SCI, locomotor recovery after SCIH was impaired in Wlds mice compared to WT animals. In conclusion, our results identify axonal degeneration as one of the triggers for collateral sprouting from the contralesional uninjured fibers after an SCIH. These results open the path for identifying molecular signals associated with tissular changes after SCI that promotes collateral sprouting and functional recovery. (C) 2014 Elsevier Inc. All rights reserved.