An investigation was undertaken to determine if susceptibility and/or immune response to Mycobacterium tuberculosis was associated with histocompatible leukocyte antigen (HLA) phenotype frequencies of class I or II antigens. Comparisons of the HLA phenotypes of 51 Mexican-American patients with tuberculosis and 54 healthy subjects who differed in their skin-test reactivity to purified protein derivative (PPD) revealed that HLA-DR3 was significantly decreased in patients with tuberculosis, compared with healthy persons who were tuberculin skin-test positive. Although no association was observed between HLA phenotype and skin test reactivity to PPD in tuberculous patients, we did observe an increase in the HLA-A9-B40 phenotype in patients who manifested a strong in vitro proliferative response to PPD, whereas the HLA-B14-DR1 phenotype was increased in patients who exhibited a low proliferative response to this antigen.