The most accurate five-marker biosignature, comprised unstimulated levels of IFN-γ, MIP-1β and TGF-α and antigen-specific levels of TGF-α and VEGF, and diagnosed TB disease in the training sample set (n = 311; n = 122 TB, n = 189 ORD) with sensitivity of 68.9% (95% CI, 59.7–76.8%) and specificity of 83.1% (95% CI, 76.8–88.0%), and a sensitivity of 64.2% (95% CI, 49.7–76.5%) and specificity of 82.7% (95% CI, 72.4–89.9%) in the test set (n = 134; n = 53 TB and n = 81 ORD). Here, IFNG is linked to tuberculosis.