We studied the effect of an acute loading dose of diphenylhydantoin (DPH) on motor responses elicited with cortical magnetic stimulation in normal subjects. DPH increased significantly the motor threshold activation of ADM, APB, FDI and biceps. The motor threshold increase was of greater magnitude for the proximal muscle. Spinal soleus alpha-motoneuron pool excitability assessed by H-reflex was increased significantly suggesting that the motor threshold increase is related to a supraspinal effect of the drug. Our study demonstrates that the motor threshold increase observed after DPH administration occurs not only in epileptic patients but also in normal subjects.