Rationale: To improve the effectiveness of tuberculosis (TB) control programs in the United States by identifying cost-effective priorities for screening for latent tuberculosis infection (LTBI). Objectives: To estimate the cost-effectiveness of LTBI screening using the tuberculin skin test (TST) and interferon-g release assays (IGRAs). Methods: A Markov model of screening for LTBI with TST and IGRA in risk-groups considered in current LTBI screening guidelines. Measurements and Main Results: In all risk-groups, TST and IGRA screening resulted in increased mean life expectancy, ranging from 0.03-0.24 life-months per person screened. IGRA screening resulted in greater life expectancy gains than TST. Screening always cost more than not screening, but IGRA was cost-saving compared with TST in some groups. Four patterns of cost-effectiveness emerged, related to four risk categories. (1) Individuals at highest risk of TB reactivation (close contacts and those infected with HIV): the incremental cost-effectiveness ratio (ICER) of IGRA compared with TST was less than $100,000 per quality-adjusted life year (QALY) gained.(2) The foreign-born: IGRA was cost-saving compared with TST and cost-effective compared with no screening (ICER ,$100,000 per QALY gained). (3) Vulnerable populations (e.g., homeless, drug user, or former prisoner): the ICER of TST screening was approximately $100,000-$150,000 per QALY gained, but IGRA was not cost-effective. (4) Medical comorbidities (e.g., diabetes): the ICER of screening with TST or IGRA was greater than $100,000 per QALY. Conclusions: LTBI screening guidelines could make progress toward TB elimination by prioritizing screening for close contacts, those infected with HIV, and the foreign-born regardless of time living in the United States. For these groups, IGRA screening was more costeffective than TST screening.Keywords: latent tuberculosis; cost-effectiveness; tuberculin skin test; interferon-g release assay Reactivation of latent tuberculosis infection (LTBI) accounts for approximately 70% of cases of active tuberculosis (TB) in the United States (1, 2). Screening and treatment for LTBI is therefore a cornerstone of the strategy for the elimination of TB disease in the United States (3, 4). Previous studies have examined priorities for LTBI screening and treatment, and several have found that isoniazid (INH) therapy for low-risk tuberculin reactors is cost-effective, and even cost-saving in some populations (5-8). These studies, however, used estimates of the prevalence of LTBI and rates of reactivation TB observed in the 1950s and 1960s, and may not reflect current epidemiologic trends (9-11). Furthermore, given the development of interferon-g release assays (IGRA) as a screening test for LTBI, it is important to expand the investigation to compare the effectiveness and cost-effectiveness of both tuberculin skin test (TST) and IGRA screening (4). Although prior studies have investigated the cost-effectiveness of IGRA, they focused on select risk-groups, and did not prioritize s...