In HbE, HbC, and HbOArab a glutamic acid is mutated to a lysine resulting in a cumulative increase in positive charge of +4 units per tetramer when compared to HbA. These mutations occur at β−26, β−6, and β−121, respectively. We have reported an increase in both K-Cl cotransport and in red cell density (that is directly proportional to MCHC) for HbC and HbOArab. In the case of HbC, we demonstrated that transgenic mice expressing HbC also have these properties. We also previously reported that human homozyous HbE red blood cells (hRBC) have normal red cell density; that is, they have the same MCHC as HbA hRBC. We now report that RBC from mice (mRBC) expressing HbE have elevated K-Cl cotransport and normal MCHC and that these properties have been found in HbE hRBC as well. In mice expressing exclusively human α and βE, K-Cl cotransport in mRBC with HbE versus C57Bl was 10±0.9 versus 2.0±0.9 mmol/L cells x hr (FU), respectively. Mice expressing exclusively HbE have mRBC that are microcytic vs C57 (MCV=32.9±1.5 vs 47.5±2.0 fl, N=5, p<0.0003), have low MCH vs C57 (MCH=9.8±0.1 vs 14.7±0.8 pg, N=5, p<0.0004), but have normal MCHC vs C57 (CHCM=29.7±1.1 vs 30.9±1.9 g/dl, p=NS). In a human patient with HbE β0 thalassemia, we found elevated K-Cl cotransport (10±0.9 versus 2.0±0.9 FU) and red cell indices vs HbA that were analogous to those seen in HbE transgenic mice: (MCV=63.8 vs 88.1±2.3 fl), (MCH=20.9 vs 30.9±1.0 pg), but a normal MCHC vs HbA (CHCM=33.0 vs 34.9±1.2 g/dl). Because this patient suffers from severe thalassemia and hence has an elevated reticulocyte count (17%), the elevation in K-Cl cotransport may be due, in part or totally, to the presence of reticulocytes. However, reticulocytes have a lower MCHC than mature RBC, and blood with a high percent of reticulocytes generally has a low average MCHC; however, we observed a normal MCHC for this patient and others in whom K-Cl was not measured. We attribute the normal MCHC observed in both human patients with HbE and in our transgenic mouse model to the effect of K-Cl cotransport on a red cell with a thalassemic background. In conclusion, the low MCHC anticipated from the well-known thalassemic nature of the HbE mutation is not realized due to enhanced K-Cl cotransport. This demonstrates that the mouse model reproduces the hematologic features of the human disease and will provide a suitable model for gene therapy and other therapeutic approaches for HbE hemoglobinopathies.