The beta-thalassemic mouse provides a useful model for testing hypotheses about the pathophysiology in human beta-thalassemia. The clinical picture of these mice and their red blood cell deformability characteristics are quite similar to those observed in human beta- thalassemia intermedia. The creation of transgenic mice that express human beta-globin (beta s) has provided an opportunity to study the effect of increasing the non-alpha-globin chain production on the thalassemic phenotype. A small increase in beta-globin production produces transgenic mice that are healthier, have almost normal hemoglobin values, and whose red blood cell deformability is increased. We quantified and characterized the membrane skeletal-associated globin in normal, transgenic thal/sickle, and thalassemic mice and showed that only alpha-globin was associated with the membrane skeleton in the pathologic red blood cells, and that the degree of rigidity as measured in the rheoscope correlated directly and closely with the amount of membrane skeletal-associated globin in these abnormal red blood cells.