OBJECTIVES: Metformin has shown its effectiveness in treating obesity in adults. However, little research has been conducted in children, with a lack of attention on pubertal status. The objectives were to determine whether oral metformin treatment reduces BMI z score, cardiovascular risk, and inflammation biomarkers in children who are obese depending on pubertal stage and sex. METHODS: This was a randomized, prospective, double-blind, placebo-controlled, multicenter trial, stratified according to pubertal stage and sex, conducted at 4 Spanish clinical hospitals. Eighty prepubertal and 80 pubertal nondiabetic children who were obese aged 7 to 14 years with a BMI >95th percentiles were recruited. The intervention included 1 g/d of metformin versus placebo for 6 months. The primary outcome was a reduction in BMI z score. Secondary outcomes comprised insulin resistance, cardiovascular risk, and inflammation biomarkers. RESULTS: A total of 140 children completed the study (72 boys). Metformin decreased the BMI z score versus placebo in the prepubertal group (−0.8 and −0.6, respectively; difference, 0.2; P = .04). Significant increments were observed in prepubertal children treated with metformin versus placebo recipients in the quantitative insulin sensitivity check index (0.010 and −0.007; difference, 0.017; P = .01) and the adiponectin–leptin ratio (0.96 and 0.15; difference, 0.81; P = .01) and declines in interferon-γ (−5.6 and 0; difference, 5.6; P = .02) and total plasminogen activator inhibitor-1 (−1.7 and 2.4; difference, 4.1; P = .04). No serious adverse effects were reported. CONCLUSIONS: Metformin decreased the BMI z score and improved inflammatory and cardiovascular-related obesity parameters in prepubertal children but not in pubertal children. Hence, the differential response according to puberty might be related to the dose of metformin per kilogram of weight. Further investigations are necessary.