Background: The role of protein families PE/PPE remains relatively enlightening. The gene rv3429, coding the PPE59 protein, is one of the 12 members of the PPE subfamily, and it is absent in all BCG strains. Although elicits low T cell response, there are no clues for the ability to induce a humoral response. Methods: We cloned, expressed, and analyzed by ELISA IgG, IgM and IgA anti PPE59 in 212 sera. Of them, 69 were from tuberculosis patients’ residents in Italy (TBIT, 12 native and 67 immigrants), the remaining 133 are Brazilians citizens (BR). Pulmonary (pTBIT) or extrapulmonary (eTBIT) clinical forms were 54 or 25. The pTBBR were 52 and 81 non-TB patients, including 10 non-tuberculous mycobacteria infected (NTM). Results: Keeping the specificity at 97%, IgA sensitivity decreased from pTBBR (53%) to pTBIT (38%) and eTBIT (28%), with an overall sensitivity of 42.7% and moderate accuracy (61.8 %), while IgG showed significant lower (p<0.0001) performance, 21%, 3%, 0%, 9% and 37%, respectively, at specificity of 83%. Groups were not discriminate by IgM. False-positive NTM IgG was high. Combination 16kDa IgG, previously performed only on Bazilians’ sera, plus PPE 59 IgA results increased sensitivity to 71% at 87.4% specificity. The overall smear microscopy (SM) diagnosis was 70.8% and a combination of SM/IgA increased sensitivity to 74% (p=0.01), mainly among SM- cases. Among pTBBR, all these rapid tests, including SM, sensitivity reach 86.5% (p=0.001). Positive IgA polarization was significant in extensive lung disease (p=0.001) and alcohol users (p=0.04). Conclusion: Although PPE59 IgA independently has moderate accuracy on TB diagnosis, together with other biomarkers contributes to improving its detection. Moreover, the polarized reactivity deserves further investigation.