We have examined the alpha globin gene complex for 49 individuals with alpha-thalassemia-2 (-alpha 3.7). Crossovers resulting in alpha-thalassemia-2 (type I) were observed in all 57 chromosomes with the -alpha 3.7 defect. Except for one alpha-thalassemia-2 chromosome, all were linked to the absence of an Rsa I restriction site located 0.7 kb 5' to the alpha 2-globin gene; this polymorphic site was observed for 10 of 38 non-alpha-thalassemia chromosomes from Black Americans. In four Black families with a heterozygous alpha-thalassemia-2 [-alpha 3.7 (I)], an Apa I restriction site has been identified in the IVS-2 of the alpha 2 gene of the normal chromosome (labeled the alpha *2 gene). The alpha *2 gene of one Black subject was cloned and a segment located 5' to the Cap site as well as the IVS-2, exon 3, and a 3' segment were sequenced. The data show that the alpha *2 gene is an alpha 2 gene except for a segment between nucleotides (nts) 580-81 and nt 509 (Cap site = nt 1), and perhaps as far upstream as nt -634, which has an alpha 1 sequence. This alpha *2 hybrid gene probably originated through a double crossover; the structural identity of its IVS-2 with that of the alpha 1 gene adequately explains the presence of the Apa I restriction site.