Chronic periodontitis is the most common chronic inflammatory disease and has been associated with an increased risk for serious medical conditions including cardiovascular disease (CVD). Endotoxin (lipopolysaccharide), derived from periodontopathogens, can induce the local accumulation of mononuclear cells in the inflammatory lesion, increasing proinflammatory cytokines and matrix metalloproteinases (MMPs), resulting in the destruction of periodontal connective tissues including bone. In this study, we show that doxycycline, originally developed as a broad-spectrum tetracycline antibiotic (and, more recently, as a nonantimicrobial therapy for chronic inflammatory periodontal and skin diseases), can inhibit extracellular matrix degradation in cell culture mediated by human peripheral blood-derived monocytes/macrophages. The mechanisms include downregulation of cytokines and MMP-9 protein levels and the inhibition of the activities of both collagenase and MMP-9. These pleiotropic, but nonantibiotic, effects of doxycycline explain, at least in part, its therapeutic potential for various chronic inflammatory diseases including periodontitis, and may reduce the risks of systemic diseases (e.g. CVDs, less manageable diabetes) associated with this and other local diseases.