Adrenocorticotropic hormone is recommended worldwide as an initial therapy for infantile spasms. However, infantile spasms in about 50% of children cannot be fully controlled by adrenocorticotropic hormone monotherapy, seizures recur in 33% of patients who initially respond to adrenocorticotropic hormone monotherapy, and side effects are relatively common during adrenocorticotropic hormone treatment. Topiramate, vitamin B 6 , and immunoglobulin are effective in some children with infantile spasms. In the present study, we hypothesized that combined therapy with adrenocorticotropic hormone, topiramate, vitamin B 6 , and immunoglobulin would effectively treat infantile spasms and have mild adverse effects. Thus, 51 children newly diagnosed with West syndrome including infantile spasms were enrolled and underwent polytherapy with the four drugs. Electroencephalographic hypsarrhythmia was significantly improved in a majority of patients, and these patients were seizure-free, had mild side effects, and low recurrence rates. The overall rates of effective treatment and loss of seizures were significantly higher in cryptogenic children compared with symptomatic children. The mean time to loss of seizures in cryptogenic children was significantly shorter than in symptomatic patients. These findings indicate that initial polytherapy with adrenocorticotropic hormone, topiramate, vitamin B 6 , and immunoglobulin effectively improves the prognosis of infantile spasms, and its effects were superior in cryptogenic children to symptomatic children. However, infantile spasms in about 50% of children can not be fully controlled by adrenocorticotropic hormone monotherapy, seizures recur in 33% of patients who initially respond to adrenocorticotropic hormone monotherapy, and side effects Topiramate, vitamin B 6, and immunoglobulin are effective in some children with infantile spasms. In the present study, we hypothesized that combined therapy with adrenocorticotropic hormone, topiramate, vitamin B 6, and immunoglobulin wouldfficient treat Thus, 51 children newly diagnosed with West syndrome including infantile spasms were enrolled and underwent polytherapy with the four drugs. Electroencephalographic hypsarrhythmia was significantly improved in a majority of patients, and these patients were seizure-free, had mild side effects, and low recurrence rates. The overall rates of effective treatment and loss of seizures were significantly higher in cryptogenic children compared with symptomatic children. The mean time to loss of seizures in cryptogenic children was significantly shorter than in symptomatic patients. initial polytherapy with adrenocorticotropic hormone, topiramate, vitamin B 6, and immunoglobulin effectively improves the prognosis of infantile spasms, and its effects were superior in cryptogenic children to symptomatic children.