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The objective of this study was to identify blood-based protein biomarkers of early stage Mycobacterium tuberculosis (Mtb) infection. We utilized plasma and serum specimens from TB patients and their contacts (age ≥ 12) enrolled in a household contact study in Uganda. In the discovery phase cross-sectional samples from 104 HIV-uninfected persons classified as either active TB, latent Mtb infection (LTBI), tuberculin skin test (TST) converters, or persistent TST-negative were analyzed. Two hundred eighty-nine statistically significant (false discovery rate corrected p 0.85. Panel performance was confirmed with an independent validation set of longitudinal samples from 16 subjects. These candidate protein biomarkers may allow for the identification of recently Mtb infected individuals at highest risk for developing active TB and most likely to benefit from preventive therapy., Highlights • Changes in host proteins can be detected in M. tuberculosis infection, even prior to tuberculin skin test conversion. • Early M. tuberculosis infection provoked host responses related to inflammation, immune-response, and lipid metabolism. • Protein panels were able to predict tuberculin skin test conversion and development of latent M. tuberculosis infection. Developing a diagnostic test that identifies recent M. tuberculosis infection would allow for targeted treatment of those persons most likely to progress to active tuberculosis (TB). Current tests for M. tuberculosis infection are unable to differentiate between latent M. tuberculosis infection (LTBI) and active TB, nor distinguish recent from remote infection. This study identified human host proteins capable of predicting tuberculin skin test conversion, and the development of LTBI. These candidate protein biomarkers may allow for the identification of recently Mtb infected individuals who are at highest risk for developing active TB and would most benefit from preventive therapy.