Hb H disease is rarely seen in individuals of African descent although α-thalassemia (α-thal) is common in this population. Usually α-thal is due either to heterozygosity or homozygosity for the -α(3.7) deletion in this population. We report Hb H disease that is caused by a frameshift mutation on one -α(3.7) allele in two unrelated individuals homozygous for the -α(3.7) deletion. These two cases highlight the importance of further investigation by direct sequencing of the -α(3.7) allele when the thalassemic phenotype does not correlate with the genotype obtained by initial molecular testing.