Interleukin-18 (IL-18) has multiple important pro-inflammatory effects, including the induction of interferon-gamma (IFN-gamma) in various diseases. In this study, we investigated the IL-18-producing activities in human pulmonary and pleural tuberculosis (TB) in response to purified protein derivative (PPD) antigen (Ag) from Mycobacterium tuberculosis. The most significant IL-18 production was found in chronic refractory TB (CRTB) patients. However, IFN-gamma production in CRTB patients was significantly less than that in healthy tuberculin reactors or in patients with tuberculous pleurisy (TBP). Elevated levels of both IL-18 and IFN-gamma were found in pleural fluids from TBP patients. In vitro production of IL-18 was dramatically decreased following an 18 h stimulation with PPD. However, IFN-gamma was markedly increased in pleural mononuclear cells from TBP patients after in vitro stimulation with PPD. The mesothelial cell type was the main source of pro-IL-18 in pleural cells from TBP patients, suggesting an important role for these cells in TBP. Taken together, these data indicate that IL-18 is elevated in peripheral blood mononuclear cells from CRTB patients, as well as at the site of TBP, indicating a possible role for IL-18 in both protective immunity and pathologic responses in human TB.