Fifty-nine patients with chronic generalized toniclonic or partial seizures refractory to the maximally tolerated daily dosage of single-drup therapy with carbamazepine, phenytoin, phenobarbital, or primidone subsequently received single-drug therapy with another one of these primary anticonvulsant drugs. Alternative single-drug therapy resulted in complete seizure control or more than 75% seizure reduction for 18 patients (31%). Side effects disappeared in 16 patients (27%). Patients with a good therapeutic response often had epilepsy of recent onset. Alternative single-drug therapy is beneficial for chronic refractory epilepsy and should be considered before a second drug is permanently added.