Objective To evaluate costs and cost-effectiveness to the healthcare system, and costs to families, of a national prenatal exome sequencing (pES) service additional to standard testing, compared to standard testing alone. Design A cost-effectiveness analysis combining costs, outcomes, parent and professional interview and professional survey data. Setting The English National Health Service (NHS) Genomic Medicine Service. Sample 413 cases referred for pES testing from 01/10/2021 to 30/06/2022. Methods We costed the incremental resource required to deliver the pES clinical pathway, synthesising this with unit costs and outcomes data on additional cases diagnosed to analyse cost-effectiveness. We estimated the annual NHS budget requirement based on case numbers. We determined parental costs from interviews. Main Outcome Measures Incremental costs of pES to the NHS and families, incremental cost per additional diagnosis, NHS budget impact. Results Of 413 referred cases, 241 were tested, at a cost of £2,331 (95% credibility interval £1,894-£2,856) per referred case, or £3,592 (£2,959-£4,250) per case that proceeded with testing. The incremental cost per diagnosis (yield 35.3%) was £11,326 (£8,582-£15,361). At current demand levels pES costs the NHS approximately £1.7m annually. Family costs could not be separated from other pregnancy related appointments but were not considered burdensome as most appointments were concurrent or remote. Conclusions pES is more expensive than predecessor prenatal genetic testing technologies, has a higher diagnostic yield and informs pregnancy management and decision making. Further research into potential savings from the foregone diagnostic odyssey resulting from pES may be informative.