Although the development of hemolytic anemia as a complication of acute copper intoxication is well documented, the precise mechanism by which copper produces accelerated erythrocyte destruction is unknown. Normal erythrocyte survival depends in part on the ability of the cell to deform and pass through narrow areas of microcirculation in the liver and especially in the spleen. In the present study, it is demonstrated that toxic concentrations of copper rapidly and markedly reduce erythrocyte deformability. This reduction in cell deformability is associated with a marked increase in membrane permeability and osmotic fragility of copper-treated cells. Further, the decrease in deformability occurs despite normal levels of cell ATP and the apparent absence of oxidative damage to the cell. These observations indicate that copper-mediated changes in the erythrocyte membrane may be responsible for reducing the flexibility of the cell. The loss of deformability could act to reduce erythrocyte survival and thus explain the hemolysis associated with copper intoxication in vivo.