This study aimed to estimate the cost-effectiveness of the use of recombinant zoster vaccine (RZV) (Shingrix), which protects against herpes zoster (HZ), among immunocompromised adults aged 19 to 49 years, as a contribution to deliberations of the Advisory Committee on Immunization Practices. Hematopoietic cell transplant (HCT) recipients experience a high incidence of HZ, and the efficacy of RZV in preventing HZ has been studied in clinical trials. The cost-effectiveness model calculated incremental cost-effectiveness ratios that compared vaccination with RZV with a no vaccination strategy among adults aged 19 to 49 years. Costs and outcomes were calculated until age 50 years using the healthcare sector perspective and summarized as cost per quality-adjusted life-year (QALY) gained. The base case represents HCT recipients, with scenario analyses representing persons with other immunocompromising conditions, including hematologic malignancies, human immunodeficiency virus, and autoimmune and inflammatory conditions. Uncertainty was investigated using univariate, multivariate, and probabilistic sensitivity analyses. Base-case results indicated vaccination with RZV would avert approximately 35% of HZ episodes and complications, while saving approximately 11% of net costs. Compared with no vaccination, vaccination of HCT recipients with RZV generated cost-savings (ie, lower costs and improved health) in the base case and in 81% of simulations in the probabilistic analysis. In scenario analyses, vaccination cost US dollar ($) 9500/QALY among patients with hematologic malignancies, $79 000/QALY among persons living with human immunodeficiency virus, and $208 000/QALY among persons with selected autoimmune and inflammatory conditions. Generally favorable economic estimates supported recommendations for vaccination of immunocompromised adults with RZV to prevent episodes of HZ and related complications. •In a cost-effectiveness analysis, the use of recombinant zoster vaccine (RZV) among adults aged 19 to 49 years who received a hematopoietic cell transplant was found to be cost-saving in the base-case scenario and in most sensitivity analyses. Scenario analyses investigating persons with other selected immunocompromising conditions resulted in a wide range of economic values.•Generally favorable economic estimates further support that vaccination of immunocompromised adults with RZV should be a clinical priority to prevent episodes of herpes zoster and related complications.•In October 2021, RZV (Shingrix) was recommended for use among immunocompromised adults aged ≥ 19 years.