Background <p>Previous studies have suggested that factors such as the treatment interval and aetiology may influence the initial response rate to first-line treatment for infantile epileptic spasms syndrome (IESS). However, few children with IECSS have undergone clinically accessible tests to determine the aetiology.</p> Methods <p>Using a dataset from our previously published research, we constructed and tested a predictive model for the initial response to first-line treatment in children with IESS. Random sampling and 5-fold cross-validation were performed, with synthetic minority oversampling technique to correct data imbalance. Machine learning algorithms and evaluation metrics optimised model accuracy and efficacy.</p> Results <p>This study included 532 children with IESS who had completed monotherapy first-line treatment, of whom 160 achieved an initial response. The model’s accuracy, F1 score, and area under the curve (AUC) in the validation set were 0.7836 ± 0.0229 (ranging from 0.75167 to 0.80536), 0.7833 ± 0.0229 (ranging from 0.75145 to 0.80531), and 0.8516 ± 0.0165 (ranging from 0.82468 to 0.86936), respectively. Factors such as the age of seizure onset, age of spasm onset, lead time, MRI subtype, treatment choice, and age at treatment consistently ranked in the top six for importance in contributing to the model.</p> Conclusions <p>The study findings suggest that this model may help effectively predict the initial response to first-line treatment, supporting clinical decision-making for children with IESS. Key predictors such as the age of seizure onset and MRI subtype enable early, data-driven intervention strategies in clinical practice.</p>