Background: Despite progress in tuberculosis (TB) control in low-burden countries like England and Wales, there are still diagnostic delays. Molecular testing and/or whole-genome sequencing (WGS) provide more rapid diagnosis but their cost-effectiveness is relatively unexplored in low-burden settings. Methods: An integrated transmission-dynamic health-economic model is used to assess the cost-effectiveness of using WGS to replace culture-based drug-sensitivity testing, vs using molecular testing vs combined use of WGS and molecular testing, for routine TB diagnosis. The model accounts for the effects of faster appropriate treatment in reducing transmission, benefiting health and reducing future treatment costs. Cost-effectiveness is assessed using Incremental Net benefit (INB) over a 10-yearhorizon with a Quality-Adjusted Life-Year valued at £20,000, and discounting at 3.5%p.a.ResultsWGS shortens the time to drug-sensitivity testing, and treatment modification where necessary, reducing treatment and hospitalization costs, with an INB of £7.1M. Molecular testing shortens the time to TB diagnosis and treatment. Initially this causes an increase in annual costs of treatment, but averting transmissions and future active-TB disease subsequently resulting in cost savings and health benefits to achieve an INB of £8.6M(GeneXpert MTB/RIF) or £11.1M(Xpert-Ultra) respectively. Combined use of Xpert-Ultraand WGS is the optimal strategy we consider, with an INB of £16.5M. Conclusions: Routine use of WGS or molecular testing is cost-effective in a low-burden setting, and combined use is the most cost-effective option. Adoption of these technologies can help low-burden countries meet the WHO End TB Strategy milestones, particularly the UK, which still has relatively high TB rates.