The thalassemias are inherited disorders classified genetically into α, β, γ, δβ, δ and εγδβ varieties according to the type of globin(s) that are underproduced. At the molecular level, the εγδβ thalassemias fall into two categories; Group I removes all, or a greater part, of the β globin gene cluster which is embedded in an array of olfactory receptor genes on chromosome 11p15. Group II removes extensive upstream regions leaving the β globin gene itself intact despite which, its expression is silenced due to inactivation of the upstream locus control region (β LCR). Recently, two novel deletions causing εγδβ thalassemia have been reported; a 153 kb deletion removing the entire β globin cluster in a Chilean family (Game, L., et al., Br J Haematol 2003, 123:154–9) and an upstream deletion of 112 kb in a Dutch family (Dutch III) (Harteveld, C.L., et al., Br J Haematol 2003, 122: 855–8). We describe here the characterization of another three novel εγδβ thalassemia deletions, in three English families, named English II, III and IV, to differentiate them from the previously reported English (I) deletion (Curtin, P., et al., J Clin Invest 1985, 76: 1554–8). Deletion English II removed 98 kb extending 90 kb upstream of the ε gene to 8 kb upstream of the Gγ gene, and included 4 upstream olfactory receptor (HOR) genes. Deletion English III removed 114 kb extending 60 kb upstream of the ε gene to 9 kb downstream of the β globin gene, thus including the entire β globin gene cluster as well as two upstream HOR genes. English IV is the largest deletion (439 kb) reported so far; starting 326 kb upstream of the ε gene to 70 kb downstream of the β gene and included 13 upstream, and 3 downstream, HOR genes plus the intervening β globin gene cluster. Breakpoints of all the 3 deletions occurred within regions of L1 or Alu repeat elements and contained short regions of direct homology between the flanking sequences, a feature that is likely to have contributed to the illegitimate recombinations. Deletions English II and III appear to be de novo while English IV is not. The proband for the English IV deletion had neonatal hemolytic anemia and required blood transfusions while 3 other family members who were heterozygous for the same deletion, had uneventful post-natal periods. The English III proband also required a blood transfusion soon after birth while the English II proband did not. Although in later life, heterozygotes for εγδβ thalassemia are transfusion-independent, and have a blood picture typical of β thalassemia trait but with normal Hb A2 levels, our data suggest that heterozygotes for εγδβ thalassemias have more severe microcytosis and hypochromia than β thalassemia carriers. To date, a total of 15 deletions causing εγδβ thalassemia have been described - five upstream deletions (Group II) associated with intact β globin genes and ten (Group I) that include the entire β globin gene cluster. These deletions are all unique and illustrate the heterogeneity of the εγδβ thalassemias.