BACKGROUND: An increasing proportion of novel drug approvals use accelerated pathways, with notable growth in the US Food and Drug Administration-designated breakthrough pathway in recent years. Breakthrough therapy (BT) designation suggests that these therapies offer substantial potential to improve health outcomes but their value for money is not fully understood, as BTs typically cost more than non-BTs (NBTs). OBJECTIVE: To assess the economic value of BTs and factors associated with their reported value. METHODS: Using the Tufts Medical Center Cost-Effectiveness (CE) Analysis Registry, we (1) summarized the CE of BTs, as measured by cost per quality-adjusted-life-year (QALY); (2) compared the CE of BTs and NBTs in the United States; and (3) identified factors associated with BT CE using general estimating equation models across US willingness-to-pay (WTP) benchmarks ($50K-$150K/QALY). RESULTS: Between 2013 and 2018, the US Food and Drug Administration approved 279 drugs, designating 83 (32%) as BTs. Incremental costs and health gains (QALYs) were higher for BTs relative to NBTs ($29,000 vs $20,000 and 0.7 vs 0.2 QALYs, respectively), and BTs had more favorable CE ratios compared with NBTs (median values $38,000/QALY vs $50,000/QALY, respectively). For BTs, hepatitis C treatments had the most favorable CE ratios, which may be driven by the curative nature of some hepatitis C therapies. Furthermore, BT CE ratios for new molecular entities (NMEs) were about 40% lower than ratios for non-NME BTs on average, which may signal more value for money when the BT has a new active molecule. Regression analysis to identify trends driving CE found that BT drugs compared with active comparators (instead of best supportive care) were less likely to be cost-effective at standard US WTP thresholds (odds ratio [OR] = 0.1-0.6) and that BTs in the neoplasm space also trended less likely to be cost-effective (OR = 0.12-0.43). CE ratios reported by studies with industry funding were also more likely to be cost-effective than ratios from studies with other funding sources (OR = 4.3-4.5), though this finding was not significant at WTP thresholds over $50,000/QALY gained. CONCLUSIONS: Evidence from published, peer-reviewed CE studies suggests that BTs may confer greater health benefits than NBTs in terms of overall QALYs. Our analysis supports that the US Food and Drug Administration BT designation may be associated with increased value for money for these BTs. However, factors such as the disease area, NME status, and comparator (active vs standard of care) will also influence whether these therapies are cost-effective. DISCLOSURES: Dr Cohen reports grants or contracts from PhRMA Foundation, National Pharmaceutical Council, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Gilead Sciences, Regeneron, Pfizer, Merck, Johnson & Johnson, Vir Biotechnology, Moderna, Amgen, and Lundbeck; consulting fees from AbbVie, Biogen, IQVIA, Novartis, Partnership for Health Analytic Research, Pharmerit, Precision Health Economics, Sage, Sanofi, and Sarepta; and stock or stock options from Bristol-Myers Squibb, Johnson & Johnson, and Merck. Ms Kowal is an employee and stockholder of Genentech, Inc. Dr Yeh is an employee and stockholder of Roche, Inc.