To determine if the capacity to produce interferon (IFN) gamma is related to the clinical manifestations of tuberculosis, we correlated Mycobacterium tuberculosis-induced IFN-gamma production by peripheral blood mononuclear cells (PBMCs) with clinical, radiographic, and laboratory variables for 63 human immunodeficiency virus (HIV)-negative patients and 43 HIV-positive patients with tuberculosis. For HIV-negative patients whose chest radiographs showed moderately advanced disease, the mean IFN-gamma concentration +/- SD was 1,639 +/- 388 pg/mL, whereas that for patients with far-advanced disease was 327 +/- 100 pg/mL (P = .0001). For HIV-infected patients who had only pleuropulmonary disease, the mean IFN-gamma concentration was 1,002 +/- 257 pg/mL, whereas that for patients with disease outside the lungs and pleura was 149 +/- 55 pg/mL (P = .0004). Multivariate analysis confirmed that the radiographic extent of disease and the site of disease were the only independent predictors of IFN-gamma production in HIV-negative and HIV-infected patients (P < or = .001). We conclude that reduced IFN-gamma production by PBMCs is a marker of severe tuberculosis in both HIV-negative and HIV-infected patients with tuberculosis.