Molecular studies have demonstrated that the incidence ofα-thalassemia heterozygotes in Greece is approximately 8%: theα+ deletion (-α3.7) accounting for 7% and 3α0 deletions for about 1%. Characterization ofα-thalassemia genotypes in 67 HbH disease patients demonstrated extreme heterogeneity of α-thalassemia mutations. Eleven different genotypes resulted from the interaction of 4 deletion and 7 nondeletionα-thalassemia mutations. Forty three individuals had deletion genotypes, 14 were compound heterozygotes for a0 deletions and nondeletion genotypes and 10 had nondeletion genotypes. A strong correlation between phenotype and genotype was noted, with nondeletion genotypes associated with a more severe clinical course and higher HbH levels (>12%); complications and transfusion requirements were rare. Exceptionally HbH patients with either Hblcaria (termination > Lys) or HbAgrinio (CD29Leu>Pro) had atypical phenotypes. HbH-Hblcaria (3 cases--Med/αIcα) showed severe clinical manifestations in infancy with bone changes, growth impairment, splenomegaly and anemia necessitating blood transfusions for survival. Splenectomy (at 7-8 years) resulted in marked amelioration of clinical signs and post splenectomy all three patients preserve 9-10g/dl Hb. Two patients with αAgrα/αPASaudiα and 1 HbAgrinio homozygote were diagnosed in infancy with splenomegaly, severe anemia (Hb<7g/dl) necessitating transfusion but paradoxically very low levels HbH (<5%). The most atypical case was the HbAgr homozygote with marked anemia, slight splenomegaly, Hb that fluxed between 6-8g/dl and notably the presence of only trace levels of HbH. This report emphasises the extreme heterogeneity of the α-thalassemia syndromes in Greece and the phenotype/genotype correlation.