Although both differential susceptibility to Mycobacterium tuberculosis infection and disease pathogenesis depend on a multitude of factors, elucidation of specific host genetic markers, particularly those in the human major histocompatibility complex, is important. The present study is an attempt to delineate human leukocyte antigen (HLA) class I association in tuberculosis (TB) on the basis of a shared sequence motif in peptide-binding pockets of HLA molecules. In patients with pulmonary TB and miliary/disseminated TB, we observed significantly increased frequencies of A3-like supertypes and decreased frequencies of A1-like supertypes. These 2 positively and negatively associated supertypes (allele groups) share a similar peptide-binding motif, except for residues in pocket F of the HLA class I molecules. In addition, the HLA-Cw specificities that are major ligands for killer cell immunoglobulin-like (inhibitory) receptors (KIRs), particularly KIR2DL1 (Cw2, Cw4, and CW5) and KIR2DL2 (Cw1, Cw3, and Cw7), were found more frequently among patients with TB, which suggests a possible inhibition of natural killer cell activity against the infected target cells. The results of the present study suggest that the frequent occurrence of HLA class I specificities comprising an A3-like peptide-binding motif and the increased occurrence of ligands for KIR2DL in TB together may influence the outcome of TB.