The potassium (K+) channel-blocking agent 4-aminopyridine (4-AP) is currently being investigated for its potential therapeutic value in patients with spinal cord injury (SCI). The present study was designed to test the hypothesis that 4-AP ameliorates central motor conduction deficits in individuals with SCI. Oral 4-AP (10 mg) was administered to 19 (n = 19) SCI subjects with stable neurological deficits. Their response to the drug was monitored using motor evoked potentials (MEPs) following transcranial magnetic stimulation of motor cortex and various measures of segmental or peripheral reflex activity (F-waves, H-reflex, and M-response) recorded from lower limb muscles. The mean MEP amplitude in the extensor digitorum brevis muscle (left) was significantly (p < .05) increased from x = .25 +/- .42 mV to x = .59 +/- 1.04 mV at 2 h after drug administration, and the cortical stimulation threshold was reduced (p < .05) by 5.8%. Similar results were obtained in all subjects exhibiting MEPs (n = 13) and in all muscles (n = 6) studied. These changes were maintained at 4 h postdrug. MEP latencies were reduced in all subjects who initially exhibited abnormally prolonged MEP latencies relative to control group (n = 13) values. F-wave, H-reflex, and M-response values (latency and amplitude) were not systematically altered by 4-AP, leading to the conclusion that it was central motor conduction that was enhanced. This interpretation was supported by observed reductions in central motor conduction time (CMCT) in the majority of SCI subjects from whom CMCT measurements were obtained, two of whom anecdotally reported improved motor control after 4-AP, and by increased MEP:M-wave amplitude ratios. The MEP:M-wave ratios indicated that the magnitude of the effect of 4-AP on motoneuron recruitment was not large, in absolute terms (<4% motoneuron pool), but was appreciable relative to the initial level of motoneuron recruitment. These results provide the first statistically significant, objective evidence of improved functioning of the neuromuscular system in chronically injured SCI subjects receiving 4-AP and suggest that the improvements are mediated through enhanced central conduction. The results further support the emerging view that pharmaceutical management of central conduction deficits may prove to be a useful therapeutic strategy for some patients with long-standing SCI.