Early identification of newborns with congenital cytomegalovirus (CMV) is necessary to provide antiviral therapy and other interventions that can improve outcomes. Prior research demonstrates that universal newborn CMV screening would be the most cost-effective approach to identifying newborns who are infected. CMV is not uniformly prevalent, and it is uncertain whether universal screening would remain cost-effective in lower-prevalence neighborhoods. Our aim was to identify geographic heterogeneity in the cost-effectiveness of universal newborn CMV screening by combining a geospatial analysis with a preexisting cost-effectiveness analysis. This study used the CMV testing results and zip code location data of 96 785 newborns in 7 metropolitan areas who had been tested for CMV as part of the CMV and Hearing Multicenter Screening study. A hierarchical bayesian generalized additive model was constructed to evaluate geographic variability in the odds of CMV. The zip code-level odds of CMV were then used to weight the results of a previously published model evaluating universal CMV screening vs symptom-targeted screening. The odds of CMV were heterogeneous over large geographic scales, with the highest odds in the southeastern United States. Universal screening was more cost-effective and afforded more averted cases of severe hearing loss than targeted testing. Universal screening remained the most cost-effective option even in areas with the lowest CMV prevalence. Universal newborn CMV screening is cost-effective regardless of underlying CMV prevalence and is the preferred strategy to reduce morbidity from congenital CMV.