The efficacy of zonisamide (ZNS) was studied in 16 patients (11 males, 5 females) with West syndrome (WS), symptomatic in 13 and cryptogenic in 3. They did not respond to pyridoxal phosphate (12 cases) or valproate (16 cases). The mean age of onset of WS was 4.4 (2-9) months. ZNS was administered from 3 to 9 months of age (mean 6.1). Four cases (2 cryptogenic and 2 symptomatic) became seizure free. Two had more than 50% seizure reduction. Ten infants remained unchanged or showed less than 50% seizure reduction. In the 4 responders, the effective dose was 4-8 mg/kg (mean 5.8), and the serum ZNS concentration was 10-21 micrograms/ml (mean 13.8). One had relapse of WS after 4 months. Three with normalized EEG remained seizure-free during the follow-up period (12-26 months). One case developed a transient drowsiness, but no serious side effects were observed. These data suggest ZNS may be regarded as a therapy of choice before synthesized ACTH therapy in the management of WS.