Severe, but reversible, hemolytic anemia occurred in a patient with profound hypophosphatemia (serum phosphorus less than 0.1 mg per 100 ml). Red-cell ATP and 2,3 DPG were markedly depressed during the hypophosphatemic period (to 11 and 30 per cent of normal, respectively). The striking reduction in red-cell ATP was associated with microspherocytic morphology, increased rigidity and diminished survival of the affected cells. All variables returned to normal after parenteral phosphate supplementation. The more than twofold increase in rigidity of ATP-deficient red cells was corrected by incubation with adenosine for two hours, so as to generate intracellular ATP. In addition to the hemolytic process, tissue oxygenation was probably further curtailed during the hypophosphatemic period because of the lowered red-cell 2,3 DPG and ATP levels. Hypophosphatemia may thus have profound, deleterious effects on the viability of human red cells.