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This study aims to explore the association between frailty scores (FS) and latent tuberculosis infection (LTBI) and analyze the impact of FS on all-cause mortality in the LTBI population, providing a reference for optimizing screening strategies in high-risk groups. A total of 3520 adults aged 18 to 79 years from the National Health and Nutrition Examination Survey 2011 to 2012 cycle were included, comprising 564 individuals in the LTBI group and 2956 in the non-LTBI group. LTBI was diagnosed through a combination of the tuberculin skin test and interferon-gamma release assays. The FS was constructed based on 53 health deficit indicators covering cognitive function, comorbidities, nutritional metrics, and laboratory parameters. The natural logarithm of FS was generated as natural logarithm of FS (LnFS). A multivariable logistic regression model was used to analyze the association between LnFS and LTBI, while Cox proportional hazards models assessed its impact on all-cause mortality. A mediation analysis was performed with LnFS as the exposure, LTBI as the outcome, and serum globulin concentration as the hypothesized mediator. The FS score was notably greater in the LTBI group than in the non-LTBI group (0.15 ± 0.09 vs 0.13 ± 0.08; P = .003). The association between LnFS and LTBI was stronger (odds ratio = 1.26, 95% confidence interval: 1.05-1.52, P = .016). Globulin partially mediated the link between LTBI and FS (12.5% mediation effect, P = .04). The risk of all-cause mortality was increased by 32% in LTBI patients (hazard ratio = 1.32, 95% confidence interval: 1.05-1.66), and this risk intensified in a dose-dependent manner with increasing FS scores (interaction P = .02). FS are significantly positively correlated with LTBI, and this relationship accelerates the frailty process through chronic inflammatory responses mediated by globulin. FS independently increases the risk of all-cause mortality. The findings provide scientific evidence for early frailty screening and targeted interventions in high-risk LTBI populations, while emphasizing the importance of serum globulin levels.