OBJECTIVE: To estimate the cost-effectiveness of screening overweight and obese individuals for pre-diabetes and then modifying their lifestyle based on the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS: A Markov simulation model was used to estimate disease progression, costs, and quality of life. Cost-effectiveness was evaluated from a health care system perspective. We considered two screening/treatment strategies for pre-diabetes. Strategy 1 included screening overweight subjects and giving them the lifestyle intervention included in the DPP if they were diagnosed with both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Strategy 2 included screening followed by lifestyle intervention for subjects diagnosed with either IGT or IFG or both. Each strategy was compared with a program of no screening. RESULTS: Screening for pre-diabetes and treating those identified as having both IGT and IFG with the DPP lifestyle intervention had a cost-effectiveness ratio of $8,181 per quality-adjusted life-year (QALY) relative to no screening. If treatment was also provided to subjects with only IGT or only IFG (strategy 2), the cost-effectiveness ratio increased to $9,511 per QALY. Changes in screening-related parameters had small effects on the cost-effectiveness ratios; the results were more sensitive to changes in intervention-related parameters. CONCLUSIONS: Screening for pre-diabetes in the overweight and obese U.S. population followed by the DPP lifestyle intervention has a relatively attractive cost-effectiveness ratio.