RATIONALE: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection. OBJECTIVES: To identify a functional role of platelets in the innate inflammatory and matrix degrading response in TB. METHODS: Markers of platelet activation were examined in plasma from 50 TB patients pre-treatment, and 50 controls. 25 patients were followed longitudinally. Platelet-monocyte interactions were studied in a co-culture model infected with live, virulent Mycobacterium tuberculosis (M.tb) and dissected using qPCR, Luminex multiplex arrays, matrix degradation assays and colony counts. Immunohistochemistry detected CD41 expression in a pulmonary TB murine model and secreted platelet factors were measured in bronchoalveolar lavage fluid (BALF) from 15 TB patients and matched controls. MEASUREMENTS AND MAIN RESULTS: Five of six platelet-associated mediators were upregulated in plasma of TB patients compared to controls, with concentrations returning to baseline by day 60 of treatment. Gene expression of the monocyte collagenase MMP-1 was upregulated by platelets in M.tb infection. Platelets also enhanced M.tb-induced MMP-1 and -10 secretion which drove Type I collagen degradation. Platelets increased monocyte IL-1 and IL-10 and decreased IL-12 and monocyte-derived chemokine (MDC, also known as CCL-22) secretion, as consistent with an M2 monocyte phenotype. Monocyte killing of intracellular M.tb was decreased. In the lung, platelets were detected in a TB mouse model and secreted platelet mediators were upregulated in human BALF, and correlated with MMP and IL-1β concentrations. CONCLUSIONS: Platelets drive a pro-inflammatory, tissue-degrading phenotype in TB.