Alpha-cristobalite causes pulmonary interstitial disease in humans and experimental animals. Aerosol exposure of rats to cristobalite for 8 days results in early and sustained alveolar type II cell hyperplasia in areas of inflammation characterized by the presence of macrophages and polymorphonuclear leukocytes. Irregular interstitial fibrosis and coalescence of alveoli are apparent by day 120. The inflammatory response is characterized by increased lavage cell recoveries, principally macrophages and neutrophils. Lavage recoveries of protein, nonpolar lipid, phospholipid, and saturated phosphatidylcholine also are increased. The recovery ratio for two important surfactant phospholipids, phosphatidylcholine and phosphatidylglycerol, is decreased at all points following exposure. Our morphologic analyses, together with results correlating lavage cell and lipid recoveries, point to the potential importance of macrophages and neutrophils in the epithelial cell response to cristobalite exposure.