Isolated rat hepatocytes were exposed to CCl4 in doses commonly used in in vitro studies and for which we have provided biochemical evidence would induce solvent injury. Rapidly evolving morphologic alterations were observed in the plasma membrane, endoplasmic reticulum, and mitochondria. Swelling and fusion of surface microvilli with formation of blebs were particularly prominent and occurred within 2 min of exposure. Blebs regressed in some hepatocytes without evidence of cell death, when these cells were exposed to CCl4 under conditions promoting its evaporation. Disorganization of endoplasmic reticulum and mitochondrial injury were also prominent early findings. Rapid appearance of diffuse ultrastructural alterations in isolated hepatocytes exposed to CCl4 is consistent with nonspecific membrane injury induced by solvent effects.