Interleukin-8 (IL-8) plays an important role in the host immune response to Mycobacterium tuberculosis by recruiting inflammatory cells to the site of infection. Here, we investigated the role of pleural macrophages and mesothelial cells in the production of IL-8 in tuberculous pleurisy. Large concentrations of IL-8 were detected in tuberculous pleural effusions, but not in pleural effusions associated with congestive heart failure (CHF). Tuberculous pleural macrophages and M. tuberculosis-infected CHF pleural macrophages produced large concentrations of IL-8. When immunohistochemistry was performed on pleural tissues, antigenic IL-8 was detected in the mesothelial cells lining the tuberculous pleura. Direct stimulation of cultured CHF pleural mesothelial cells with M. tuberculosis induced IL-8 secretion. However, conditioned media from M. tuberculosis-infected pleural macrophages (CoMTB) induced greater mesothelial cell IL-8 secretion. Tumour necrosis factor-alpha (TNF-alpha) and IL-1beta induced mesothelial cell IL-8 mRNA expression, and neutralizing anti-TNF-alpha antibody and IL-1 receptor antagonist nearly completely obliterated CoMTB-induced mesothelial cell IL-8 mRNA expression and protein secretion. These findings demonstrate that both pleural macrophages and mesothelial cells produce IL-8 in tuberculous pleurisy, and cytokines produced by M. tuberculosis-infected macrophages mediate mesothelial cell IL-8 production.