Spherocytosis is an auto-hemolytic anemia (a disease of the blood) characterized by the production of red blood cells (RBCs), or erythrocytes, that are sphere-shaped, rather than donut-shaped or, more specifically, bi-concave disk shaped. It is caused by a molecular defect in one or more of the proteins of the red blood cell cytoskeleton (usually ankyrin, sometimes spectrin). Because the cell skeleton has a defect, the blood cell contracts to its most surface-tension efficient and least flexible configuration, a sphere, rather than the more flexible donut-shape. The sphere-shaped red blood cells are known as spherocytes.

Though the spherocytes have a smaller surface area through which oxygen and carbon dioxide can be exchanged, they in themselves perform adequately to maintain healthy oxygen supplies. However, they have a high osmotic fragility--when placed into water, they are more likely to burst than normal red blood cells. These cells are more prone to physical degradation. They are most commonly found in immunologically-mediated hemolytic anemias and in hereditary spherocytosis, but the former would have a positive direct Coombs test and the latter would not. The misshapen but otherwise healthy red blood cells are mistaken by the spleen for old or damaged red blood cells and it thus constantly breaks them down, causing a cycle whereby the body destroys its own blood supply (auto-hemolysis).