BACKGROUND: The progression from Mycobacterium tuberculosis infection to active tuberculosis disease varies among individuals, and identifying biomarkers to predict progression is crucial for guiding interventions. In this study, we aimed to determine plasma immune biomarker profiles in healthy household contacts of index patients with pulmonary tuberculosis, who either progressed to tuberculosis or remained as nonprogressors. METHODS: A cohort of household contacts of adults with pulmonary tuberculosis was enrolled, consisting of 15 contacts who progressed to tuberculosis disease and 15 nonprogressors. Plasma samples were collected at baseline, 4 months, and 12 months to identify predictive tuberculosis progression markers. RESULTS: Our findings revealed that individuals in the progressor group exhibited significantly decreased levels of interferon (IFN) γ, tumor necrosis factor α, interleukin 2, IL-1α, IL-1β, and 17A, and interleukin 1 receptor antagonist (IL-1Ra) at baseline, month 4, and month 12. In contrast, the progressor group displayed significantly elevated levels of IFN-α, IFN-β, interleukin 6 and 12, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 10 (IL-10) and 33 (IL-33), CCL2, CCL11, CXCL8, CXCL10, CX3CL1, vascular endothelial growth factor, granzyme B, and programmed death ligand -1 compared to the nonprogressor group at baseline, months 4 and 12. Receiver operating characteristic analysis (ROC) identified IFN-γ, GM-CSF, IL-1Ra, CCL2, and CXCL10 as the most promising predictive markers, with an area under the receiver operating characteristic curve of ≥90. Furthermore, combinatorial analysis demonstrated that GM-CSF, CXCL10, and IL-1Ra, when used in combination, exhibited high accuracy in predicting progression to active tuberculosis disease. CONCLUSIONS: Our study suggests that a specific set of plasma biomarkers, GM-CSF, CXCL10, and IL-1Ra, can effectively identify household contacts at significant risk of developing tuberculosis disease. These findings have important implications for early intervention and preventive strategies in tuberculosis-endemic regions.