Pyruvate kinase deficient red blood cells have an abnormal tendency to lose ATP when exposed to low pO2 or cyanide, whereas normal red cells do not. Once energy is depleted, all red cells take up calcium and subsequently lose intracellular potassium and water. It has been shown previously that quinine will inhibit the potassium and water flux seen in energy depleted normal cells. The present study indicates that quinine protects cyanide treated pyruvate kinase deficient erythrocytes from water and potassium loss. Quinine does not prevent ATP depletion or calcium uptake. By six hours, cyanide treated pyruvate kinase deficient cells have lost an average of 486 gm of water per kilogram cell solids and 140 mmoles of potassium per kilogram of cell solids, while cells treated with both quinine and cyanide have lost only 106 gm of water per kilogram of cell solids and 77 mmoles of potassium per kilogram of cell solids. These data support the concept that the membrane lesion in pyruvate kinase deficiency is secondary to ATP depletion and is a manifestation of the Gardos effect. Quinine may have therapeutic potential in the treatment of pyruvate kinase deficiency hemolytic anemia.