HLA-DR allelic variants have been associated with tuberculosis (TB) susceptibility in different populations with risk ratios of 3.7 to 7.2. We hypothesized that the genetic susceptibility to TB depends upon the reduced capability of HLA-class II alleles of TB patients to bind and select peptide antigen from the Mycobacterium tuberculosis (MTB) expressed genome. To test this hypothesis, we developed a software that can predict HLA-DR restricted epitopes within the whole MTB genome based on quantitative peptide binding matrices. We analyzed the number of MTB epitopes recognized in two previously described populations of TB patients and matched controls and in a control population comprised of individuals affected by a sarcoid-like granuloma induced by beryllium and by healthy exposed controls. The number of putative epitopes within the whole MTB genome which could be bound by any HLA-DR allele (HLA-DR immunome of MTB) was 405,422 out of 1,304,277 possible 9-mers i.e., 31.08% of the global capability, instead of the expected 35%. When tested at an affinity level equivalent of the 1% of the best binder peptides, the HLA-DR alleles (HLA-DRB1*0801, *0802, *1401, *1501 and *1502) associated with TB susceptibility recognized a significantly lower mean number of MTB-epitopes (7,862 +/- 4,258) than the MTB-epitopes recognized by HLA-DR alleles (HLA-DRB1*0301, *0701, *1101, *1102, *1301 and *1302) negatively associated with TB (11,376 +/- 1,984, p<0.032). The number of epitopes bound at high affinity out of the whole MTB genome by the combination of the two HLA-DR alleles carried by each individual was lower in TB patients [TB-population 1: 11,341 +/- 908 (mean+SEM); TB-population 2: 15,303 +/- 657] than in matched healthy controls (CTR-population 1: 13,587 +/- 605, p<0.03 vs TB-population 1; CTR-population 2: 1,6841 +/- 555, p<0.04 vs TB-population 2). No difference was seen in individuals with the sarcoid-like granuloma induced by beryllium compared to the exposed healthy (beryllium-hypersensitivity: 17,593 +/- 447; controls 18,014 +/- 421; p=0.57). The data suggest that HLA-DR alleles associated with susceptibility to tuberculosis may be endowed with a reduced capability to bind at high affinity T-cell epitopes and select them for antigen presentation. The same alleles may contribute to determine the reaction to mycobacteria in non tuberculous granulomatous disorders.