Increased plasma membrane permeability, cell swelling, and cell death are consequences of metabolic energy deprivation. Rabbit retinas were incubated in an oxygenated artificial cerebrospinal fluid containing glucose. The incubating medium was modified by causing anoxia and glucose deprivation with one of the following treatments: addition of 97 mM mannitol, equimolar substitution of choline+ for Na+, or substitution of isethionate- for Cl-. Some retinas were resupplied with oxygen and glucose to determine the consequences of solute manipulation. Water compartments and membrane permeability were assayed using [3H]inulin and [14C]mannitol. Abnormal nuclei were counted on blind-coded slides. Both treatments prevented doubling of inulin-free water of untreated retinas after 70 min of deprivation. Neither treatment preserved morphology or prevented massive swelling after restoration of oxygen and glucose and gradual removal of the treatment. Mannitol leaked into deprived cells only, even when swelling was prevented. We conclude that prophylaxis of cell swelling during metabolic energy deprivation prevents neither cell leakiness nor cell death.