Objective: Approximately 12.4 million people in the U.S. have latent tuberculosis infection (LTBI), 73% of whom are non-U.S. born. Identification and treatment of LTBI are essential for tuberculosis eradication. We evaluated an emergency department (ED) – based LTBI screening and linkage to care program. Methods: We queried electronic records of a clinical prevention program located in a Midwestern, urban, academic ED that serves as the region's safety-net hospital. Program staff approached non-U.S. born ED patients from TB endemic areas. Patients received QuantiFERON-TB Gold Plus (QFT) blood testing and, if positive, were referred to treatment. The primary outcome was the proportion of tested patients newly diagnosed with LTBI. We secondarily report the number of patients linked to care who initiated LTBI treatment. Results: The program approached 33 patients, of whom 24 (72.7%) were eligible, and 23 (95.8%) were tested. The majority were male (13, 56.5%), median age was 33 years (IQR 27–45), and 13 (56.5%) were from Latin America. Three patients (13.0%, 95% CI 0.03–0.35) were newly diagnosed with LTBI and linked to care; two (66.7%) started LTBI treatment. Conclusions: In this first report of an ED-based LTBI screening program implemented in a region with low TB prevalence, over 10% of high-risk ED patients tested positive for LTBI and were linked to treatment. Screening populations at risk for LTBI in EDs and linking them to public health treatment services should be prioritized in order to achieve TB elimination in the U.S.