Direct measurements of pleural fluid hydrostatic and colloid osmotic pressures after infusion of saline, bovine serum albumin, or silicone into the pleural space were coupled with ultrastructural morphometric analyses to assess the response of pleural mesothelial cells to hydrothorax. Increases of hydrostatic pressure, either independent or in combination with decreases of osmotic pressure, served to increase the number of plasmalemmal vesicles in mesothelial cells of both the visceral and parietal pleurae. These results support the hypothesis that an increase in vesicle numerical density represents a response to elevations of extracellular fluid pressures. Fluid resorption from the pleural space with subsequent accumulation within the visceral pleural interstitium was also associated with the formation of invaginations of the mesothelial basal plasmalemma. That the invaginations were not observed in the absence of interstitial fluid accumulation supports the concept that basal surface invaginations represent distortions of mesothelial cell membranes in response to pressure differentials across the plasmalemma. The results of this study are most consistent with the interpretation that increased numbers of plasmalemmal vesicles and invaginations of the basal plasmalemma represent adaptive conformational mechanisms of pleural mesothelial cells to prevent monolayer disruption by elevated extracellular fluid pressures.