BACKGROUND: Newborns who are prenatally exposed to methadone are at risk for neonatal abstinence syndrome and the associated excess weight loss and poor weight gain. This pilot feasibility study aimed to evaluate early caloric enhancement on weight patterns among infants born to women receiving methadone maintenance therapy while pregnant. METHODS: In this double-blind pilot feasibility study, we randomly assigned infants with fetal methadone exposure to 24 or 20 kcal/oz formula from days 3 to 21. Randomization was stratified by any breastfeeding, sex of the infant, and gestational age. Eligible infants were ≥35 weeks' gestation and weighed ≥2200 g. Outcomes were days to weight nadir, maximum percent weight loss, days to birth weight, percentage weight change per day, and feasibility. RESULTS: A total of 49 infants were randomly assigned (22 to standard- and 27 to high-calorie formula); groups had comparable demographic characteristics. Main outcomes comparing standard- to high-calorie formula groups were not significant (days to weight nadir, 5.0 vs 4.4 days; P = .20; maximum percent weight loss, -9.4% vs -8.6%; P = .15; days to birth weight, 14.7 vs 13.6 days; P = .07); however, in longitudinal analyses (days 4 to 21), the high-calorie group had a higher percent weight gained per day compared with the standard-calorie group (P <.001). There were high levels of protocol adherence, and no adverse effects were observed. CONCLUSIONS: Study findings suggest that early initiation of high-calorie formula for infants with prenatal methadone exposure may be beneficial for weight gain; evaluation in a larger study is warranted.