Spinal cord transections were performed in wild type and NG2 proteoglycan null mice in order to study penetration of regenerating axons into the scar that forms in response to this type of injury. Aside from the presence or absence of NG2, the features of the transection scar did not differ between the two genotypes. In both cases, the rostral and caudal spinal cord stumps were separated by collagenous connective tissue that was continuous with the spinal cord meninges. In wild type mice, oligodendrocyte progenitors, macrophages, and microvascular pericytes contributed to up-regulation of NG2 expression in and around the scar. Substantial amounts of non-cell associated NG2 were also observed in the scar. The abilities of two classes of spinal axons to penetrate the transection scar were examined. Serotonergic efferents and calcitonin gene-related peptide-positive sensory afferents both were observed within the lesion, with calcitonin gene-related peptide-positive axons exhibiting a greater capability to penetrate deeply into the scar tissue. These observations demonstrate inherent differences in the abilities of distinct types of neurons to penetrate the scar. Significantly, growth of serotonergic axons into the transection scar was observed twice as frequently in wild type mice as in NG2 knockout mice, suggesting a stimulatory role for the proteoglycan in regeneration of these fibers. These findings run counter to in vitro evidence implicating NG2 as an inhibitor of nerve regeneration. This work therefore emphasizes the importance of including in vivo models in evaluating the responses of specific types of neurons to spinal cord injury.