IMPORTANCE Congenital cytomegalovirus (cCMV) infection is a major cause of childhood deafness. Most cCMV infections are not diagnosed without newborn screening, resulting in missed opportunities for directed care. OBJECTIVE To estimate the cost-effectiveness of universal and targeted newborn cCMV screening programs compared with no cCMV screening. DESIGN, SETTING, AND PARTICIPANTS Modelswere constructed using rates and outcomes from prospective cohort studies of newborn cCMV screening in US postpartum care and early hearing programs. Costs of laboratory testing, treatment, and hearing loss were drawn from Medicaid data and published estimates. The benefits of cCMV screening were assumed to come from antiviral therapy for affected newborns to reduce hearing loss and from earlier identification of hearing loss with postnatal onset. Analyses were performed from July 2014 to March 2016. INTERVENTIONS Models compared universal or targeted cCMV screening of newborns with a failed hearing screen, with standard care for cCMV infection. MAIN OUTCOMES AND MEASURES The incremental costs of identifying 1 cCMV infection, identifying 1 case of cCMV-related hearing loss, and preventing 1 cochlear implant; the incremental reduction in cases of severe to profound hearing loss; and the differences in costs per infant screened by universal or targeted strategies under different assumptions about the effectiveness of antiviral treatment. RESULTS Among all infants born in the United States, identification of 1 case of cCMV infection by universal screening was estimated to cost 2000 to 10 000; by targeted screening, 566 to 2832. The cost of identifying 1 case of hearing loss due to cCMV was as little as 27 460 by universal screening or 975 by targeted screening. Assuming a modest benefit of antiviral treatment, screening programs were estimated to reduce severe to profound hearing loss by 4.2%to 13%and result in direct costs of 10.86 per newborn screened. However, savings of up to 37.97 per newborn screened were estimated when costs related to functionality were included. CONCLUSIONS AND RELEVANCE Newborn screening for cCMV infection appears to be cost-effective under a wide range of assumptions. Universal screening offers larger net savings and the greatest opportunity to provide directed care. Targeted screening also appears to be cost-effective and requires testing for fewer newborns. These findings suggest that implementation of newborn cCMV screening programs is warranted.