Abstract25‐yr old female identical twins of Italian‐American origin concordant for sickle β‐thalassemia were studied to explain their clinical differences. One of them has been severely affected from childhood with one aplastic crisis, an earlier onset of vaso‐occlusive crises, and recent cardiac decompensation; the other twin shows no cardiac decompensation.Similar are their degree of anemia, RBC indices, blood volumes, absence of splenic sequestration, depression of pO2, elevation of p50 and 2,3‐DPG, hemoglobin composition, and peripheral blood globin‐synthetic rates.Regarding differences, the more severely affected has a shorter51Cr RBC life span, a greater menstrual blood loss, and is more overweight, whereas the less severely affected has functional asplenia by99mTc scanning and a larger proportion of RBC with decreased cellular deformability.We conclude that in sickle β‐thalassemia: (1) genotype alone does not determine the clinical course; (2) significant differences in clinical course can occur with almost identical hemoglobin composition and globin synthetic rates; (3) cellular deformability changes do not correlate exactly with clinical course; and (4) functional asplenia and leanness may