In this study, our objectives were to evaluate the economic feasibility of implementing selective dry cow therapy (SDCT) in large US herds and to estimate the potential reduction in antibiotic use around the dry period if SDCT management is adopted. Cow-level data were obtained from the Dairy Herd Improvement Association (AgriTech, Visalia, CA) and individual dairy herds in California. Logistic regression models were used to predict the incidence risk of subclinical and clinical mastitis in the subsequent lactation for 96 last test-day somatic cell score categories. Linear programming was used to optimize the costs of dry cow therapy in 3 simulated large US dairy herds with different bulk tank somatic cell counts (BTSCC). The objective function was aimed at minimization of the total cost of mastitis around the dry period (TCMD), under a varying constraint of the maximum percentage of cows dried off with antibiotics. A sensitivity analysis was performed on milk price, dry-off antibiotic price, and risk ratio of mastitis in the subsequent lactation when no antibiotics and only teat sealant was used at dry-off. For all situations, blanket dry cow therapy was more expensive than SDCT. In a herd with medium BTSCC, the TCMD was $54.7 per primiparous dry cow and $58.5 per multiparous dry cow annually. In the optimal economic situation where SDCT was used, only 30% of primiparous cows received antibiotics, leading to a TCMD of $52.4 per primiparous dry cow, whereas 88% of multiparous cows received antibiotics, at a cost of $58.2 per multiparous dry cow. This corresponded with an overall reduction of 29% in the use of antibiotics around the dry period in a conservative scenario. This study showed that it is economically feasible to reduce antibiotic use associated with dry cow therapy in large US dairy herds. This contributes to the efforts of reducing antibiotic use worldwide.