Benign asbestos pleurisy is a manifestation of asbestos-induced disease that is not uncommon but often ignored. We developed an animal model to study the pathogenesis of this syndrome. Crocidolite asbestos injected into the rabbit pleural space resulted in the appearance of chemotactic activity in an exudative effusion, characterized by a polymorphonuclear leukocyte (PMN) response that peaked 4 h after the injection. The chemotactic activity and the PMN responses occurred equally in normal animals and in animals that had been depleted of complement with cobra venom. Neutropenia, induced with vinblastine, did not alter the appearance of chemotactic activity but abrogated the PMN response. Treatment with colchicine failed to block the release of chemotactic activity into the pleural fluid, but decreased the PMN response without affecting the ability of peripheral blood PMN to respond to pleural fluid chemotactic activity. When pleural fluid containing chemotactic activity was injected into the pleural space of another rabbit, a PMN response was observed. These studies suggest that the acute exudative response seen in the rabbit model of benign asbestos pleurisy results from the release of chemotactic activity from sources other than complement. The response probably depends on interaction between the asbestos and the pleural tissue. Asbestos-PMN interaction may release chemotactic factors that amplify the response secondarily. Colchicine blocked the acute response to intrapleural asbestos by a mechanism yet to be understood.