Multinucleated giant cells (MGCs) are characteristic of granulomatous inflammation. Matrix metalloproteinase (MMP)-9, the major monocyte-derived matrix metalloproteinase, is key in inflammatory tissue damage. At 72 h, MGCs secrete 153 ± 2.5 ng/mL MMP-9, compared with 115 ± 3.8 ng/mL during macrophage differentiation (P < .05). In contrast, the level of MGC secretion-specific tissue inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1, is lower (P < .05). Mature MGCs secrete constitutively greater concentrations of MMP-9 than do monocytes or macrophages (P < .05). MGCs in tuberculous lymph-node biopsy samples express high MMP-9 levels adjacent to areas of necrosis, whereas TIMP-1 is not detected. Thus, MGCs are potentially important sources of MMP-9 secretion and may contribute to inflammatory tissue damage in human tuberculosis. © 2007 by the Infectious Diseases Society of America. All rights reserved.