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Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-[kappa]B, and IFN-[gamma] signaling pathways. We performed methylation- sensitive restriction enzyme-quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-[gamma] signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-[gamma], TNF, IL-6, CXCL9, CXCL10, and IL-1 p production. The DNA hypermethylation of the IL-12/IFN-[gamma] pathway was associated with decreased IFN-[gamma]-induced gene expression and decreased IL-12-inducible upregulation of IFN-[gamma]. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness., Introduction Tuberculosis (TB) continues to be a global problem, with 10 million cases and over 1 million deaths each year (1). Anti-TB therapy (ATT) requires 6 months of antibiotics, despite [...]