IMPORTANCE: Schools are considered an attractive setting to promote healthy living behaviors in children, but previous school-based interventions aimed at preventing weight gain in children have yielded mixed results. Novel school-based approaches are needed to modify healthy living behaviors and attenuate weight gain in children. OBJECTIVE: To assess the effectiveness of a peer-led healthy living program called Healthy Buddies on weight gain and its determinants when disseminated at the provincial level to elementary school students. DESIGN, SETTING, AND PARTICIPANTS: Cluster-randomized effectiveness trial performed during the 2009-2010 school year. Baseline and follow-up measurements were made in October 2009 and May 2010, respectively. The study was performed in 19 elementary schools in Manitoba, Canada, and included 647 elementary school students aged 6 to 12 years (48% girls). INTERVENTION: Schools were randomized to receive regular curriculum or Healthy Buddies lesson plans. Lesson plans were delivered by older (9- to 12-year-old) elementary school students to the younger (6- to 8-year-old) peers and targeted 3 components of health: physical activity, healthy eating, and self-esteem and body image. MAIN OUTCOMES AND MEASURES: The primary outcome measures were the change in waist circumference and body mass index z score. Secondary outcomes included physical activity (steps per day), cardiorespiratory fitness, self-efficacy, healthy living knowledge, and self-reported dietary intake. RESULTS: At baseline, 36% of children were overweight or obese and 11% achieved the recommended 13,500 steps per day. Intention-to-treat analyses showed that waist circumference declined significantly in the intervention group relative to controls: -1.42 cm (-2.68 to -0.17; P = .03). Reductions in waist circumference were particularly significant for children who were younger, overweight or obese, or attending First Nations schools. No difference in body mass index z score was observed between groups. Self-efficacy, healthy living knowledge, and dietary intake significantly improved in younger peers who received the intervention compared with students from control schools. No differences were observed in daily step counts or cardiorespiratory fitness between the groups. CONCLUSIONS AND RELEVANCE: The implementation of Healthy Buddies lesson plans delivered by older peers within an elementary school setting is an effective method for attenuating increases in central adiposity and improving knowledge of healthy living behaviors among elementary school students. Improvements were achieved with parallel improvements in diet quality, self-efficacy, and knowledge of healthy living. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01979978.