Mycobacterium tuberculosis (MTB) is a slow growing bacterium. Therefore, the immune responses associated with resolution of infection or development of disease post-exposure may take several months to evolve. We have carried out a prospective longitudinal study in a high TB transmission setting to determine the evolution of biomarkers in a recently exposed household contact (HC = 77) and their respective sputum positive index cases (TB = 17). Mycobacterium-induced cytokines [interferon-γ (IFN-γ), tumour necrosis factor-α, interleukin-6 (IL-6) and IL-10)] were assessed in whole blood cultures and immunoglobulin G (IgG1) antibodies in plasma. When compared with non-exposed community controls (endemic controls = 59) the HC group at intake showed changes in biomarkers commensurate with recent exposure. The HC group showed significant increases in IFN-γ between 0 and 6 months (paired t-test; P = 0.001) and IL-0 between 6 and 12 months (P = 0.001), most likely reflecting the role of these cytokines in resolution and immune recovery from infection as this HC cohort remained symptom-free for 4 years without prophylactic treatment. When the TB group post-treatment was compared with the HC group, the best discriminators (ANOVA; repeated measures) were IL-10 responses at 0 (P = 0.004) and 6 months (P = 0.001) and IgG1 at 6 (P = 0.004) and 12 months (P = 0.014) with a 3–4 fold higher responses in the TB group. Therefore, within each group, biomarkers show unique profile of responses. These studies highlighted the importance of assessing multiple biomarkers in longitudinal studies for providing better understanding of protective biomarker profiles associated with resolution of clinical and subclinical infections in TB.