After a lesion of the mature CNS, structural plasticity and functional recovery are very limited, in contrast to the developing CNS. The postnatal decrease in plasticity is correlated in time with the formation of myelin. To investigate the possible role of an important myelin-associated neurite growth inhibitor (NI-250; IN-1 antigen), one pyramidal tract of adult Lewis rats was lesioned (pyramidotomy), and the rats were treated with the antibody IN-1, a control antibody, or no antibody. Functional recovery was studied from postoperative day 14 until day 42 using a food pellet reaching task, rope climbing, and a grid walk paradigm. The corticofugal projections to the red nucleus and basilar pontine nuclei were analyzed after survival times of 2 and 16 weeks. Treatment with the monoclonal antibody IN-1 resulted in almost complete restoration of skilled forelimb use, whereas all the control groups showed severe and chronic impairments. This functional recovery was paralleled by sprouting of the corticorubral and the corticopontine fibers across the midline, thus establishing a bilateral, anatomically specific projection.