OBJECTIVES: Infantile spasms (IS) are severe epileptic encephalopathy during infancy. The SCN1A encodes the alpha 1 subunit of the neuronal voltage-gated sodium channels, and mutations in SCN1A have been frequently detected in idiopathic epilepsy and encephalopathy, which had similar symptoms as IS. Therefore, we investigated the association of SCN1A polymorphism with the IS and the responsiveness to adrenocorticotropic hormone (ACTH) treatment in the present study. PATIENTS AND METHODS: We totally collected 113 IS patients and and 122 age-matched healthy controls. All of the subjects were Han Chinese descent, and the 113 cases were further divided into subgroups of cryptogenic and symptomatic patients. Nine tag SNPs within the SCN1A gene were selected and genotyped by the direct sequencing of PCR-amplified products. The ACTH was then applied to all of the cases. RESULTS: Two SNPs in high linkage disequilibrium, rs13397210 and rs760543, were significantly associated with IS under genotype model (p = 0.015). In addition, we also found that a 4-SNP haplotype (CAGC) which contains the aforementioned 2 SNPs, was associated with increased responsiveness to ACTH therapy in IS (p = 0.018, OR = 4.8) under recessive model. Of the 2 subgroups of cases, more cryptogenic patients responded to the ACTH treatment than the symptomatic patients. CONCLUSIONS: The results suggested that genetic variants of the SCN1A gene were associated with IS and ACTH responsiveness.