Objective To explore the influence factors and predictors of treatment response after adrenocorticotropic hormone (ACTH) in infantile epileptic spasms syndrome(IESS). Methods A retrospective analysis was conducted on 80 cases of IESS infants(50 males and 30 females) who were diagnosed and treated with ACTH in Chengdu Women's and Children's Central Hospital from January 2016 to December 2020. Patients were divided into effective group (n=39) and ineffective group (n=41) based on their response of ACTH treatment after 28 days, and their clinical data including the patients' basic information, etiology, treatment programmer, per- and post-treatment Kramer scores of electroencephalogram (EEG) hypsarrhythmia severity and so on, were collected to compare and analyze between the two groups. A modified Poisson regression model was constructed to discover predictors of outcome, and the receiver operating characteristic (ROC) curves were used to assess the prognosis evaluation of the positive predictive value. Results The ages at seizure onset ranged from one month and seven days to one year and nine months. Seizure types included simple epileptic spasms in 66 cases and combined with other types(focal and secondarily generalized seizures) in 14 cases. Thirty-two cases had been given anti-seizure medications (ASMs) before ACTH treatment. The median Kramer scores per-treatment and at 14 days post-treatment were 10.0 (8.3, 12.0) and 6.0 (4.0, 7.0), respectively. After ACTH treatment, 39(48.8%) cases were effective. Compared with the effective group, the ineffective group had significantly higher proportion of abnormal perinatal conditions, unknown aetiology with normal development, ASMs given before ACTH treatment, the dosages of ACTH greater than 2 U/(kg·d), combinations of two or more ASMs, poor control, and still seizure attack after ACTH treatment of 14 days (P<0.05). Additionally, the Kramer scores after ACTH treatment of 14 days in the ineffective group were also significantly higher (P<0.05). The modified Poisson regression model showed that there were significant statistic differences between the two groups on ASMs given before ACTH treatment (RR=0.546, 95%CI 0.357-0.833, P=0.005) and Kramer scores of hypsarrhythmia severity (RR=0.701, 95%CI 0.620-0.792, P<0.001),while there were no significant differences between the two groups in term of ages, gender, perinatal conditions, etiologies, seizure types, Kramer scores before treatment, time lag between onset and treatment, duration of ACTH treatment, kinds of ASMs combination. ROC curve analysis showed that only Kramer scores at 14 days after ACTH treatment could predict the treatment response with sensitivity and specificity of 92.7% and 84.6%, respectively, with Youden index of 0.773. The area under the ROC curve was 0.930 (95%CI 0.873-0.987, P<0.001) and the cut-point of the score was 6, indicating that the higher the Kramer scores at 14 days after ACTH treatment, the worse the treatment response. The treatment response rate would reduce by about 30.0% if the Kramer score increased by one point. Conclusion ASMs given before ACTH treatment may influence the treatment response. Kramer scores greater than 6 at day 14 after ACTH treatment may be used as a predictor of treatment response after ACTH in IESS patients.