INTRODUCTION: Drug-resistant epilepsy (DRE) is a challenging neurological condition in infants. Breastfeeding is widely regarded as the gold standard for infant nutrition due to its immunological and developmental benefits. However, in certain cases of genetic DRE, breastfeeding has been associated with increased seizure frequency, necessitating alternative nutritional strategies. This study represents the first investigation that evaluates the efficacy of a milk-based ketogenic diet (KD) in infants aged one to six months with genetic DRE focusing on seizure control, nutritional status, developmental progress, and safety, as measured by metabolic and biochemical parameters. As the first study of its kind, this research offers a unique contribution to the field, paving the way for further investigations into diet-based therapies for refractory epilepsy in early life. METHODOLOGY: This prospective study included eight infants with genetic DRE, aged one to six months. Baseline data on seizure frequency, nutritional status, developmental milestones, and biochemical parameters were collected. The KD was started at a 2:1 ratio based on a non-fasting KD protocol and was optimized based on need and tolerance. Nutritional status was assessed with the Strong Kids Nutrition Screening Tool. Seizure frequency was tracked daily, and urine ketone levels were monitored to confirm ketosis. Biochemical parameters were measured at baseline and after six months. Paired t-tests were used to analyze data. RESULTS: At baseline, the mean seizure frequency was 16.5/day. After six months on the KD, the mean seizure frequency decreased to 4.6/day (p <
0.001). Nutritional status improved significantly. Urine ketone levels remained consistently high. Biochemical parameters, including triglycerides and random blood sugar, showed no significant changes, confirming the diet's safety. CONCLUSION: This study demonstrates that a milk-based KD is an effective and safe treatment for reducing seizures and improving nutritional and developmental outcomes in infants with genetic DRE. Persistent ketosis, indicated by large urine ketone levels, was a reliable biomarker of diet efficacy. Regular monitoring and careful parental counseling are essential for optimizing treatment outcomes in this vulnerable population. Further research with larger cohorts is needed to refine dietary protocols for infants with DRE.