OBJECTIVES: The Alberta Project Promoting active Living and healthy Eating (APPLE) Schools has been recognized as a “best practice in preventing childhood obesity. To inform decision making on the expansion and resource allocation for such school-based program like the APPLE Schools, we evaluated its cost-effectiveness and return-on-investment following a life-course approach. METHODS: We developed a state transition model to represent the life-time progression of weight status of three groups of children who were obese, overweight or normal weight at 11 years. The model quantified impacts of the intervention in terms of prevented excess weight cases, improved quality-adjusted life years (QALY), and avoided health care costs. Both costs and QALYs were estimated to their present value using 3% discount rate. RESULTS: The incremental cost-effectiveness ratio (ICER) of the APPLE Schools program was CA$ 15,833 per 1 QALY gained, and CA$ 24,359 or 11,047 per 1 obese or overweight case prevented in adult population. Every 1,000 children intervened; the program costs CA$190,000, and the estimated saving in the health care costs is about CA$ 2.3 million, that is equivalent to a benefit-cost ratio of 13:1. The sensitivity analyses showed that the incremental cost-effectiveness of the APPLE Schools program was robust against variations of program costs and model parameters. CONCLUSIONS: The APPLE Schools program is a cost-effective intervention for obesity prevention, and promises substantial return on investment. Expanding the coverage and allocating resources towards school-based programs is central to the fight against obesity epidemic in Canada.