Objective: To evaluate the effect of adding vigabatrin (VGB) following a 7-day assessment of adrenocorticotropic hormone (ACTH) treatment on initial response in children with infantile epileptic spasms syndrome (IESS), and its safety profile. Methods: This retrospective cohort study included children with non-tuberous sclerosis complex (non-TSC)-related IESS treated with ACTH at the General Hospital of the People's Liberation Army between June 2018 and March 2025. After 7 days of ACTH treatment, patients in whom VGB was added formed the sequential treatment group; those continuing ACTH monotherapy served as the control group. We compared initial response rates between groups and analyzed outcomes among children who continued to experience epileptic spasms (ES) on day 7 . The incidence of symptomatic vigabatrin-associated brain abnormalities on MRI (VABAM) was recorded. Results: Sequential treatment significantly improved initial response rates compared with monotherapy (78.1% [25/32] vs. 41.2% [108/262]). Among children with persistent ES on day 7 , sequential VGB combination therapy significantly improved initial response rates compared with ACTH monotherapy (66.7% [14/21] vs. 13.1% [23/176]). Multifactorial analysis with propensity score matching showed a higher response rate with sequential treatment (OR=13.75; 95% CI, 4.26-44.38). Five children receiving sequential treatment developed symptomatic VABAM-like manifestations. Conclusions: Assessing ES persistence after 7 days of ACTH treatment and deciding on VGB addition may effectively improve initial response in children with non-TSC-related IESS. ACTHVGB combination may cause short-term VABAM-like manifestations, which may resolve spontaneously with dose reduction or temporary discontinuation.