Prader-Willi syndrome (PWS) is one of the most commonly recognized causes of early-onset childhood obesity. Individuals with PWS have significant hyperphagia and decreased recognition of satiety. The exact etiology of the hyperphagia remains unknown and, therefore, untreatable. We conducted a pilot, open-label study of response to metformin in 21 children with PWS and six with early morbid obesity (EMO). Participants had significant insulin resistance and glucose intolerance on oral glucose tolerance testing (OGTT) and were started on metformin for these biochemical findings. We administered the Hyperphagia Questionnaire to parents of patients before and after starting metformin treatment. Both the PWS and EMO groups showed significant improvements in food-related distress, anxiety, and ability to be redirected away from food on the Hyperphagia Questionnaire. In the PWS group, improvements were predominantly seen in females. Within the PWS group, responders to metformin had higher 2-h glucose levels on OGTT (7.48 mmol/L vs. 4.235 mmol/L; p=0.003) and higher fasting insulin levels (116 pmol/L vs. 53.5 pmol/L; p=0.04). Additionally, parents of 5/13 individuals with PWS and 5/6 with EMO reported that their child was able to feel full while on metformin (for many this was the first time they had ever described a feeling of fullness). Metformin may improve sense of satiety and decrease anxiety about food in some individuals with PWS and EMO. Positive response to metformin may depend on the degree of hyperinsulinism and glucose intolerance. Nonetheless, the results of this pilot study bear further investigation.