Background: No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to estimate the cost-effectiveness of several screening strategies. Methods: We used person-specific data from a representative sample of the US population to create a simulated population of 325 000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). Findings: Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3-9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3-9 events prevented per 1000 people), and increased the number of QALYs (93-194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2-5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0-1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10 500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15 509), screening started at 60 years of age and repeated every 3 years ($25 738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40 778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. Interpretation: In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3-5 years. Funding: Novo Nordisk, Bayer HealthCare, and Pfizer.