Background: The aim of the present study was to assess progress made in the diagnosis of pulmonary tuberculosis when evaluating B-cell responses to 16 Ag85A synthetic peptides, the recombinant antigen 85 (rAg85) and the non-recombinant PPD antigen. Methods: The B-cell responses of tuberculosis patients and healthy individuals were evaluated by an IgG-ELISA. A total of 120 individuals were included in this study. Patient groups were conformed of 20 Warao indigenous (WP) and 20 Creole non-indigenous (CP), whilst healthy control groups were composed by 40 Warao indigenous (WC) and 40 Creole non-indigenous (CC). Both control groups included 20 positive and 20 negative individuals for the tuberculin skin test (TST). Association of positive tests for each antigen, defined with receiver operator characteristics (ROC) analysis, was assessed for each population. Results: Different patterns of the B-cell responses were displayed by each population. The anti-29878 IgG method reached highest sensitivity of 95.0% (negative predictive value (NPV) = 94.4) within the Warao population, but was lowly specific, 42.5%, (positive predictive value (PPV) = 45.2), compared to highest specificity showed by the anti-29879 IgG method (100.0%, PPV = 100). Regarding the Creole population, anti-11006 IgG showed highest sensitivity of 95.0% (NPV = 90) but was lowly specific (22.5%, PPV = 38). Anti-10998 IgG was found to be the most specific (100.0%, PPV = 100), followed by the anti-PPD IgG method (90.0%, PPV = 66.7). These findings indicate that population-to-population heterogeneity of peptide antigen recognition, rather than recognition of particular antigens, is a characteristic feature of antibody responses in these two populations. Furthermore, responses to anti-29879 IgG and anti-10998 IgG were associated to inactive TB. Conclusion: Ag85A peptides were more specific than sensitive, showing that these peptides' high specificity does not stimulate primed T cells in TST+ individuals, suggesting that they might be useful in identifying population at a higher risk of latent TB reactivation.