Background: Ultrasound may be sufficient in the diagnostic evaluation of many noncalcified lesions recalled from screening digital breast tomosynthesis (DBT). In some scenarios, omission of diagnostic mammography can save healthcare costs. Purpose: To evaluate the cost-effectiveness of a strategy of ultrasound first versus of diagnostic mammography first in the diagnostic evaluation of noncalcified lesions recalled from screening DBT. Methods: Decision tree analysis was performed to compare ultrasound first versus diagnostic mammography first in the diagnostic evaluation of DBT-recalled noncalcified lesions from a U.S. healthcare system perspective with a 40-year-horizon. The analysis used probabilities and prevalence information from published single-institution prospective data, additional literature-derived estimates of diagnostic test performance, and Medicare allowable reimbursement rates. Health states were represented in a Markov chain model. Each strategy's total cost and effectiveness [in quality-adjusted life years (QALY)] were estimated. Cost-effectiveness was assessed through incremental cost-effectiveness ratios (ICER) and incremental net monetary benefit, using a willingness-to-pay (WTP) threshold of $100,000 per QALY gained. Deterministic sensitivity analyses were performed to estimate the impact of different input parameters; probabilistic sensitivity analysis with Monte Carlo simulations was performed to estimate the impact of combined uncertainty across parameters. Results: In the base-case scenario, for diagnostic evaluation of DBT-recalled noncalcified lesions, a strategy of ultrasound first, versus a strategy of diagnostic mammography first, was more cost-saving (total cost of $17,672 vs $18,323) and more effective (QALYs of 23.1309 vs 23.1306), over the 40-year horizon. Ultrasound first resulted in an ICER of +2,170,2000 and incremental net monetary benefit of $681 versus diagnostic mammography first. Therefore, ultrasound first was deemed the more cost-effective strategy at the WTP threshold. In deterministic sensitivity analyses, the most important driver of cost-effectiveness was the lost utility from delayed diagnosis, followed by relative sensitivities of ultrasound and diagnostic mammography. In probabilistic sensitivity analysis, ultrasound first was the better strategy in 93.0% of iterations. Conclusion: A strategy of ultrasound first, with or without diagnostic mammography, is more cost effective compared to a traditional strategy of diagnostic mammography first. Clinical Impact: This cost-effectiveness analysis supports growing prioritization of ultrasound as the primary method for evaluating DBT-recalled noncalcified lesions.