The α-globin Constant Spring (CS) mutation (α142 STOP → Gln; TAA → CAA) is the most prevalent non-deletional thalassemia in south East Asia and southern China. DNA diagnosis of Hb H Constant Spring (Hb H CS; 2 α-gene deletions and 1 CS mutation) is often required because it can be missed by electrophoresis. The clinical phenotype of Hb H CS is more severe than classical Hb H disease. We sought to characterize the unique hematological and clinical features of Hb H CS patients, especially compared to those with Hb H disease, who were identified through the Thalassemia Clinical Research Network (TCRN). A total of 836 patients enrolled in the TCRN registry in Canada and the U.S. (2001 to 2005) were screened for this analysis. Genotyping of 836 thalassemia patients identified 106/836 (12.7%) with Hb H and 46/836 (5.5%) with Hb H CS. 2 had other non-deletional mutations. Among Hb H CS patients, 48% were female; mean age was 13±11 years. Among patients who had spleens, splenomegaly was more prevalent in Hb H CS than Hb H patients (16% vs 1%, p=0.001). Among Hb H CS patients who had splenomegaly, average spleen span was 3.67 ± 2.25cm. 13% of the Hb H CS and 2% of the Hb H patients had their spleen removed (p=0.005). Mean Hb level was higher in the splenectomized Hb H CS patients than in the non-splenectomized Hb H CS patients (9.85 ± 2.25 g/dL vs. 8.25 ± 0.76 g/dL, p=0.006). Post-splenectomy portal vein thrombosis was reported in 1 Hb H CS patient. 7.5% (3/40) of non-splenectomized Hb H CS patients had bacteremia or infections requiring intravenous antibiotics. 8.7% (4/46) of Hb H CS patients underwent cholecystectomy. 24% of HbH CS and none of the Hb H patients were placed on regular transfusions (>8/year) and chelation therapy. Mean age of initiation of transfusions was 3.5±1.3 years (range 2–5 years). Mean ferritin level was higher in the non-transfused Hb H CS patients than in the Hb H patients (369.9 ± 409.9 ng/ml vs 175.9 ± 304.2 ng/ml, p=0.01), suggesting increased gastrointestinal iron absorption in Hb H CS. In 5 transfused Hb H CS patients, liver iron concentration was obtained showing elevated levels (27.2 ± 13.9 μgm/gm dry wt). Growth delay was more apparent in the Hb H CS patients (n=19) compared to 20 Hb H patients (Mean height Z score: −1.34 ± 0.98 for Hb H CS vs −0.82 ± 1.15 for Hb H (p=0.16) and mean weight Z score: −1.15 ± 0.88 for Hb H CS vs. −0.83 ± 1.61 for Hb H (p=0.47)). Bone density scans in Hb H CS patients revealed a higher prevalence of low bone mass than that detected in Hb H patients: mean L1-L4 spine Z/T-score of −1.60 ± 0.86 vs. −0.93 ± 0.80 (p=0.02). 40% (4/10) of adult female Hb H CS patients had 1 or more successful pregnancies, some requiring transfusion support through pregnancy.Patients with Hb H CS have a severe phenotype of α-thalassemia. They have moderately severe anemia, which sometimes requires regular transfusions, splenectomy, or both. Patients with Hb H CS commonly have iron overload, growth delay, and reduced bone mass. Early diagnosis in the neonatal period, regular monitoring, and appropriate treatment considerations for initiation of regular transfusions are key.