Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB. Tuberculosis (TB) is a symptomatic disease caused by replicating Mycobacterium tuberculosis (Mtb). According to the WHO global tuberculosis report 2018 (https://www.who.int/tb/publications/global_report/en/), about 23% of the world's population is estimated to be latently infected with Mtb, Of these, up to 10% of humans develop active disease after Mtb infection 1 , which makes TB a major global health problem with the estimation of 10.4 million new cases and 1.7 million deaths in 2016 2. Importantly, 40% of estimated TB cases remain to be undiagnosed 2. Rapid detection of active TB is critical to reduce TB-related death. Recently-introduced interferon gamma release assay (IGRA) has better specificity than tuberculin skin test (TST) in TB screening and now become the standard for the identification of Mtb sensitization 1. Nevertheless, IGRA does not differentiate between active TB and resolved/latent infection 3. At present, sputum smear or culture of Mtb is still a gold standard for diagnosis of active TB. In addition, sputum culture is also a major biomarker for the evaluation of treatment 1,4,5. However, sputum test is assessable only when sputa of good quality were obtained from patients. Accordingly, sputum test is unavailable for infants with TB and patients with extrapulmonary tuberculosis. In addition, sputum test is not always available in resource-poor settings. Moreover, the sputum culture is not suitable for rapid decision making during therapy of outpatients, given that it requires long time before obtaining results 1. To detect Mtb in sputa in a rapid turnaround time, molecular diagnostics such as the GeneXpert MTB/RIF assay may be applicable 5. Nevertheless, this assay is ex...