Managing West syndrome (WS) becomes arduous in regions where access to adrenocorticotropic hormone and vigabatrin is limited, particularly in developing nations. This study aimed to evaluate the efficacy of very high-dose oral prednisolone in children diagnosed with WS. Children aged 2-36 months presenting with WS were consecutively enrolled and given oral prednisolone @ 8 mg/kg/day (maximum 40 mg) for two weeks followed by tapering doses over the subsequent two weeks. Weekly follow-ups were conducted until therapy completion, followed by bi-weekly assessments for three months. Responses (primary outcome) were assessed at two weeks and categorized as complete (spasm-free), partial (>
25% reduction), or no response (<
25% reduction). Neurodevelopmental outcomes, clinical-radiological profiles, safety, and therapy response predictors were also assessed. Of the 80 children, 73.7% exhibited a complete response, while 21.2% and 5% showed partial and no response, respectively. The mean age at spasm onset and presentation was 4.98 ± 4.37 months and 14.36 ± 7.13 months, respectively. Perinatal brain injury accounted for 87.5% of WS cases. Adverse effects, including weight gain (8.7%), irritability, hypertension, and disturbed sleep (3.7% each), were noted. Spasm cessation at 2 weeks, appropriate gestational age, and the absence of other seizure types were predictive of a favorable response. High-dose oral prednisolone emerges as an effective, low-cost, and safer first-line treatment option with minimal adverse effects in the Uttar Pradesh region in India, and this would likely be true in other resource-limited settings.