Background: Much has been done to promote population-based childhood asthma screening; however, concerns remain regarding its cost-effectiveness. Objectives: To conduct a cost-effectiveness analysis of school-based asthma screening strategies. Methods: A 5 health state Markov approach (symptom-free, symptom, exacerbation recovery, emergency department, and hospitalization day) was used to evaluate school-based screening in a simulated population of urban elementary-age school children. Two questionnaire and 2 multistage strategies incorporating spirometry or spirometry with exercise testing were evaluated from the societal perspective by using 365 daily cycles. The outcome was 2006 dollars per quality-adjusted life year (QALY). Results: The most efficient strategy identified children with previously diagnosed but poorly controlled asthma at a cost of $150,000 per QALY (95% CI, $65,800-$318,000). Uncertainty surrounding the cost-effectiveness estimate was primarily a result of the symptom day preference weight estimate (44%), the probability of confirmation after screening (17%), the adequacy of asthma control in the population (9%), and the estimated treatment effect on symptoms (6%). Screening generated an additional 21 symptom-free day equivalents per child identified with previously diagnosed but not well controlled asthma and led to $85.55, $12.36, and $2.58 in additional screening, daily treatment, and indirect costs and $5.01 less in emergency department and hospitalization costs. Conclusion: Population-based asthma screening is not cost-effective at $50,000 per QALY and has only a 20% chance of being cost-effective at $100,000 per QALY. The most efficient approach is to screen for previously diagnosed but poorly controlled asthma. Linking screening with better treatment, and long-term adherence strategies might yield future cost-effective approaches. © 2010 American Academy of Allergy, Asthma & Immunology.