After ischemic stroke, partial recovery of function frequently occurs and may depend on the plasticity of axonal connections. Here, we examine whether blockade of the Nogo-NogoReceptor (NgR) pathway might enhance axonal sprouting and thereby recovery after focal brain infarction. Mutant mice lacking NgR or Nogo-AB recover complex motor function after stroke more completely than do control animals. After a stroke, greater numbers of axons emanating from the undamaged cortex cross the midline to innervate the contralateral red nucleus and the ipsilateral cervical spinal cord; this axonal plasticity is enhanced in ngr ؊/؊ or nogo-ab ؊/؊ mice. In rats with middle cerebral artery occlusion, both the recovery of motor skills and corticofugal axonal plasticity are promoted by intracerebroventricular administration of a function-blocking NgR fragment. Behavioral improvement occurs when therapy is initiated 1 week after arterial occlusion. Thus, delayed pharmacological blockade of the NgR promotes subacute stroke recovery by facilitating axonal plasticity.