Host-cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here, we describe the first histone acetylome-wide association study (HAWAS) of an infectious disease, based on genome-wide H3K27 acetylation profiling of peripheral granulocytes and monocytes from subjects with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Chinese discovery cohort, which were validated in a subsequent multi-ethnic cohort, thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression in a third cohort. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulated Akt-mTOR signaling and promoted Mtb clearance in vitro. We performed histone acetylation QTL analysis on the dataset and identified candidate causal variants for immune phenotypes. Our study serves as proof-ofprinciple for HAWAS to infer mechanisms of host response to pathogens.