AbstractRed blood cell alloimmunization and consequent delayed hemolytic transfusion reaction (DHTR) incidence and mortality in patients with sickle cell disease (SCD) are high. A shared transfusion resource has decreased both in other countries, while in the United States cost concerns persist. We conducted a Markov cohort simulation of a birth cohort of alloimmunized patients with SCD to estimate lifetime DHTR incidence, DHTR‐specific mortality, quality‐adjusted life expectancy (QALE), and costs with the implementation of a shared transfusion resource to identify antibody history versus without (i.e., status quo). We conducted our analysis using a lifetime analytic time horizon and from a United States health system perspective. Implementation of shared transfusion resource projects to decrease cumulative DHTR‐specific mortality by 26% for alloimmunized patients with SCD in the United States, relative to the status quo. For an average patient population of 32 000, this intervention would generate a discounted increment of 4000 QALYs at an incremental discounted cost of $0.3 billion, resulting in an incremental cost‐effectiveness ratio of $75 600/QALY [95% credible interval $70 200–81 400/QALY]. The results are most sensitive to the baseline lifetime medical expenditure of patients with SCD. Alloantibody data exchange is cost‐effective in 100% of 10 000 Monte Carlo simulations. The resource would theoretically need a minimum patient population of 1819 patients or cost no more than $5.29 million annually to be cost‐effective. By reducing DHTR‐specific mortality, a shared transfusion resource in the United States projects to be a life‐saving and cost‐effective intervention for patients with SCD in the United States.