To study the initial pleural cellular response to asbestos and to determine the relationship between this response and the development of pleural plaques, a model of asbestos pleurisy was developed in both normal and nitrogen-mustard-treated (neutropenic) New Zealand white rabbits. Animals were rendered neutropenic, as it has been shown that neutropenic rabbits do not develop a macrophage influx in the pleural space after the administration of either BCG or bacteria and that the pathology is different from that in normal rabbits treated in a similar fashion. Intrapleural asbestos induced an exudative effusion in normal animals within 4 h, and there was increased metabolic activity through 120 h, with a fall in pleural fluid pH and PO2 and a rise in pleural fluid PCO2. Neutropenic animals similarly developed an exudative pleural effusion but showed no change in metabolic activity of pleural fluid. Normal rabbits showed a marked cellular influx into the pleural space after asbestos treatment, with a peak total cell count of 27,208/μl at 24 h; the majority of these cells were polymorphonuclear leukocytes. A macrophage influx occurred at 48 h and peaked at 72 h. By 120 h, lymphocytes were the predominant cell. Nitrogen-mustard-treated animals reached a peak of only 5,442 cells/μl in the pleural space at 24 h, with a small percentage of polymorphonuclear leukocytes. A macrophage peak did not occur in these animals. There was a marked contrast between groups noted at autopsy. Normal animals developed pleural plaque formation, which was evident by 7 days and completely developed by 1 month. Nitrogen-mustard-treated animals did not develop pleural plaques but instead had marked fibrosis in the pleural space. It appears that the pleural macrophage is important in localizing the asbestos fiber and in the ultimate formation of the pleural plaque. When a critical number of macrophages is not present, disorganization and widespread fibrosis occur. The neutrophil-macrophage interaction may not only be pivotal to the development of pleural fibrosis but to the inflammatory response in other organs as well.