Objective: To estimate the cost-effectiveness of screening for vasa previa at 18-20 weeks gestation. Several screening strategies were considered for singleton and twin pregnancies. Methods: We constructed a decision-analytic model to estimate the incremental costs and benefits associated with screening for vasa previa at 18-20 weeks gestation. We compared the status quo of not screening to scenarios in which all singleton and twin pregnancies were screened using transvaginal color Doppler ultrasound. We also considered strategies in which only high-risk pregnancies were screened. Costs were collected primarily from the London Health Sciences Centre case costing initiative and from the OHIP Schedule of Benefits for Physicians. Other data estimates were obtained from published sources and expert opinion. Health benefits were measured in life-years (LY) gained. Costs and health benefits were estimated for a cohort of pregnancies in Ontario in 1 year. Results: Compared to not screening, screening all twin pregnancies for vasa previa has an incremental cost effectiveness ratio (ICER) of less than $10,000 per LY gained. Among all risk factors in singleton pregnancies, velementous cord insertion is the strongest predictor of vasa previa. Identifying and screening pregnancies affected by velamentous cord insertion has an ICER of less than $10,000 per LY gained compared to not screening. Compared to screening only pregnancies identified as having a velamentous cord insertion, screening all pregnancies has an ICER of approximately $75,000 per LY-gained. Compared to screening for vasa previa in pregnancies identified as having any high risk indicator, routine screening of all pregnancies has an ICER of over $100,000 per LY gained. Conclusion: A strategy of screening all twin and all high-risk singleton pregnancies for vasa previa has a very low incremental cost effectiveness ratio and should be considered for adoption. However, routine screening of all pregnancies is not likely to be cost effective.