Axonal conduction deficit is a major contributor to various degrees of disability after spinal cord injury. 4-aminopyridine (4-AP), a potassium channel blocker, has been shown to restore some conduction and improve neurological function in both animal and human studies. Utilizing a double sucrose-gap recording device we have examined the effects of 4-AP on isolated guinea pig spinal cord white matter after stretch injury. At a concentration of 100 µM, 4-AP increased the amplitude of the compound action potential by 100% while 1 µM 4-AP increased it by 43%, a larger response than seen following compression injury. The length of affected tissue is suggested as a potential explanation of this differential sensitivity to 4-AP. Plastic sections taken from the injury site revealed severe myelin damage, especially in the paranodal area, which may also partially explain why 4-AP has more effect on conduction after stretch injury than compression. In addition, we have shown that while enhancing conductivity in some axons, 4-AP significantly reduced the overall responsiveness to multiple stimuli, as evidenced by increase of the refractory period in response to dual stimuli and the decreased ability to follow repetitive stimuli. This increased refractoriness may be largely attributed to residual deficits in fibers newly recruited by 4-AP treatment.