Technical Abstract: The prevalence of childhood overweight has increased significantly, with the highest rates noted among Mexican Americans. Many negative health outcomes are associated with overweight; thus, there is a need for effective weight-loss interventions tailored to this group. This study evaluated 24-month outcomes of a randomized, controlled trial involving an intensive lifestyle-based weight maintenance program targeting overweight Mexican-American children at a charter school in Houston, Texas. A total of 60 children (33 males, 55%) between the ages of 10 and 14 at or >85th percentile for BMI were recruited. Participants were randomized to an instructor-led intervention (ILI) or a self-help (SH) program, both aimed at modifying eating and physical activity behaviors using behavior modification strategies. Changes in participants' standardized BMI (zBMI) were assessed at baseline, 1, and 2 years. Tricep skinfold, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and calculated low-density lipoprotein were assessed at baseline and 1 year. ILI participants showed significantly greater decreases in zBMI at 1 and 2 years (F = 26.8, P < 0.001, F = 4.1, P < 0.05, respectively) compared to SH controls. ILI participants showed greater improvements in body composition, as measured by tricep skinfold (F = 9.75, P < 0.01). Children in the ILI condition experienced benefits with respect to total cholesterol (F = 7.19, P < 0.05) and triglycerides (F = 4.35, P < 0.05) compared to children in the SH condition. Overall, the school-based intervention resulted in improved weight and clinical outcomes in overweight Mexican-American children, and zBMI was maintained over 2 years.