Although talc slurry pleurodesis is effective for control of malignant pleural effusions and recurrent pneumothorax, the mechanisms of pleurodesis remain incompletely defined. We instilled 70 mg/kg of sterile asbestos-free talc slurry into the pleural space of New Zealand white rabbits and studied the inflammatory response at 1, 2, 3, 7, 15, 30, 60, 90, and 120 days by observing pleural fluid and histologic characteristics. Talc slurry caused mesothelial denudement and an exudative neurotrophilic pleural effusion that resolved after 48 h. A transient mononuclear vasculitis was seen within the lung at 1, 2, and 3 days after instillation. Pleural adhesions were minimal and did not increase in number over time. Talc was found outside of the pleural space in mediastinal lymph nodes (4 of 23 animals examined), kidney (1 of 6), and spleen (4 of 10). The predominant cause of pleurodesis with talc slurry instillation is an acute pleural injury similar to the tetracycline class agents.