Soluble surface-active block copolymers of polyoxypropylene and polyoxyethylene have been widely used as suspending or wetting agents in materials for topical or oral administration. One such copolymer, Pluronic F-38 (Polyoxamer 108), has been used experimentally in a new fractionation procedure for plasma proteins. Since residual amounts of this copolymer might be administered intravenously with a plasma fraction, its toxicity was evaluated following intravenous administration. Sprague-Dawley rats were injected intravenously with 0.15, 1, 2, and 4 g/kg of Pluronic F-38 five times a week for 2 weeks. Examination of tissues by light microscopy revealed that Pluronic F-38 caused early and prominent vacuolization of epithelial cells in the proximal renal tubules and of hepatocytes, as well as a gradual accumulation of vacuoles in Type II macrophages in the lung. These alterations in morphology were dose dependent and increased in severity during the period of administration. The lesions were slowly reversible; there was a moderate decrease in vacuolization 14 days after the last injection. Transmission electron microscopy indicated that the vacuoles were probably distended lysosomes. The paucity of additional cellular changes suggests that, although Pluronic F-38 may be rapidly phagocytized, it is well tolerated even when administered intravenously in large doses.