Suspensions of erythrocytes from patients with hemoglobin (Hb) CC disease showed an increased viscosity and decreased filterability suggesting a less deformable cell. Hemolysates prepared from Hb CC erythrocytes had an increased viscosity compared with hemolysates of normal cells, suggesting that the increased viscosity of Hb CC cells in serum was the result of an increased internal viscosity of the cell. These abnormal rheological properties of Hb CC erythrocytes were associated with a decreased content of cations and an abnormality of cell water. The fraction of the cell volume, which is water in Hb CC cells, was 95.5% of normal. The amount of cell water in Hb CC cells available for osmotic equilibrium, termed solvent water, was only 67% of that in normal cells. The smaller amount of solvent water in Hb CC cells indicates a greater amount of water bound to protein. Altered rheological properties of erythrocytes with Hb AA, CC, and SC also were observed during pregnancy. Suspensions of erythrocytes in serum or plasma from pregnant patients resulted in an increased viscosity compared with suspension in serum or plasma from nonpregnant individuals. An increased viscosity during pregnancy is consistent with the increased severity of the hemolytic anemia in patients with these hemoglobinopathies during pregnancy. The studies reported here suggest that in Hb CC disease the mechanism of erythrocyte destruction, splenic sequestration, results from the increased viscosity, and less deformability of the erythrocyte with on increased internal viscosity.