To perform a cost-effectiveness analysis of prenatal screening strategies for major congenital heart disease (CHD).A decision-analytic model comparing 4 screening strategies-3 views, 5 views, 5 axial views, and 6 views-identified fetuses with major CHD in a theoretical cohort of 4,000,000 births. Outcomes related to neonatal mortality and neuro-developmental disability were calculated. The analysis was performed from a healthcare system perspective with a cost-effectiveness threshold set at $100,000 per quality-adjusted life year (QALY). Base case, one-way sensitivity analysis, and Monte Carlo simulation were performed.In our base-case model, 5-axial view screening was the optimal strategy. It detected 3520 more CHDs and resulted in 259 fewer children with neuro-developmental disability, 40 fewer neonatal deaths, and slightly higher costs compared to screening with 3 views. Screening with 6 views was more effective, but also cost more than 5 axial views, and had an incremental cost of $490,023 /QALY, which was over the willingness-to-pay threshold. The final strategy, 5 views, was more costly and less effective compared to the other three strategies. The data were robust when tested with Monte Carlo and one-way sensitivity analysis.Although current guidelines recommend 3 views as the minimum strategy for detecting CHD during the mid-trimester anatomy scan, 5 axial views is the cost-effective strategy that may lead to better outcomes than 3-view screening. This article is protected by copyright. All rights reserved.