The acute in vivo response of the visceral pleura following intracheal instillation of amosite asbestos was examined by light microscopy and by transmission and scanning electron microscopy in the guinea pig model. Asbestos fibers were observed close to the pleura in all time periods but were never found within the pleura or subpleural regions proper. Thus, pleural changes occurred in the absence of direct fiber contact. Morphological changes in the pleural and subpleural areas were seen as early as 2 h after exposure and were associated with pathological alterations of the underlying parenchyma. The normally squamous mesothelial cells became pleomorphic in experimental animals, ranging from slightly cuboidal, to protruding "columnar-like" cells, to more bizarre forms. While many organelles remained unaltered, an increase in vacuolization in portions of the pleura indicated localized and advanced intracellular responses. Beginning at 4 h postexposure, varied numbers of particulate-free macrophages were seen on the pleural surface, and were considered an extension of the inflammatory response occurring in the underlying parenchyma. Early proliferation of the mesothelial cells, in limited areas of the pleura, and cytoplasmic extensions into the pleural space were also observed. Distortions of the basal lamina and smooth-muscle bundles accompanied the morphological changes in the pleural cells. A trend toward normality was observed in the longer time frames, but some areas of pleural change persisted through 3 mo postexposure.