IMPORTANCE: Moving to multigene testing for all women with breast cancer (BC) could identify many more mutation carriers who can benefit from precision prevention. However, the cost-effectiveness of this approach remains unaddressed. OBJECTIVE: To estimate incremental lifetime effects, costs, and cost-effectiveness of multigene testing of all patients with BC compared with the current practice of genetic testing (BRCA) based on family history (FH) or clinical criteria. DESIGN, SETTING, AND PARTICIPANTS: This cost-effectiveness microsimulation modeling study compared lifetime costs and effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing of all unselected patients with BC (strategy A) with BRCA1/BRCA2 testing based on FH or clinical criteria (strategy B) in United Kingdom (UK) and US populations. Data were obtained from 11 836 patients in population-based BC cohorts (regardless of FH) recruited to 4 large research studies. Data were collected and analyzed from January 1, 2018, through June 8, 2019. The time horizon is lifetime. Payer and societal perspectives are presented. Probabilistic and 1-way sensitivity analyses evaluate model uncertainty. INTERVENTIONS: In strategy A, all women with BC underwent BRCA1/BRCA2/PALB2 testing. In strategy B, only women with BC fulfilling FH or clinical criteria underwent BRCA testing. Affected BRCA/PALB2 carriers could undertake contralateral preventive mastectomy; BRCA carriers could choose risk-reducing salpingo-oophorectomy (RRSO). Relatives of mutation carriers underwent cascade testing. Unaffected relative carriers could undergo magnetic resonance imaging or mammography screening, chemoprevention, or risk-reducing mastectomy for BC risk and RRSO for ovarian cancer (OC) risk. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained and compared with standard £30 000/QALY and $100 000/QALY UK and US thresholds, respectively. Incidence of OC, BC, excess deaths due to heart disease, and the overall population effects were estimated. RESULTS: BRCA1/BRCA2/PALB2 multigene testing for all patients detected with BC annually would cost £10 464/QALY (payer perspective) or £7216/QALY (societal perspective) in the United Kingdom or $65 661/QALY (payer perspective) or $61 618/QALY (societal perspective) in the United States compared with current BRCA testing based on clinical criteria or FH. This is well below UK and US cost-effectiveness thresholds. In probabilistic sensitivity analysis, unselected multigene testing remained cost-effective for 98% to 99% of UK and 64% to 68% of US health system simulations. One year's unselected multigene testing could prevent 2101 cases of BC and OC and 633 deaths in the United Kingdom and 9733 cases of BC and OC and 2406 deaths in the United States. Correspondingly, 8 excess deaths due to heart disease occurred in the United Kingdom and 35 in the United States annually. CONCLUSIONS AND RELEVANCE: This study found unselected, high-risk multigene testing for all patients with BC to be extremely cost-effective compared with testing based on FH or clinical criteria for UK and US health systems. These findings support changing current policy to expand genetic testing to all women with BC.