Introduction: There is emerging evidence to suggest effectiveness of oral zonisamide therapy in children with West syndrome. The objective of the present study was to elucidate the safety, feasibility and effectiveness of oral zonisamide therapy in infants with West syndrome in comparison with intramuscular ACTH therapy. Methods: Study design: Pragmatic, Randomized-controlled, open-label, non-inferiority, pilot study, concealed allocation, parallel-group assignment. Randomization was done via computer generated random table and allocation was concealed. Newly diagnosed 30 cases of West syndrome (age 6-12 months) attending the outpatient department were studied. Suspected or proven cases of tuberous sclerosis and neurometabolic disorders were excluded. The efficacy outcomes were cessation of spasms (as reported by parents) and resolution of hypsarrhythmia in EEG by day 14 after initiation of treatment and safety as incidence of side effects. The trial was approved with institute ethics committee and registered in clinical trial registry. Results: Preliminary study results revealed oral zonisamide therapy was well tolerated. By day 14 of therapy, 3/15 children had cessation of spasms in zonisamide group, but 7/15 children had cessation of spasms in ACTH group. However, by day 21 of therapy, 8/15 children had cessation of spasms in zonisamide group, but 10/15 children had cessation of spasms in ACTH group.   Conclusions: Zonisamide appears safe and feasible in infants with West syndrome but probably slower and weaker in efficacy.