We have determined haplotypes for the known restriction site polymorphisms in the beta-globin gene cluster in two families of European ancestry containing individuals who are heterozygous for hemoglobin E. In both families, the beta E mutation is associated with a haplotype not previously found among the haplotypes of beta E chromosomes in Southeast Asia. Moreover, in one family, the mutation is present in a beta-gene framework not found in beta E chromosomes of Southeast Asia. These data provide further evidence of multiple independent origins of the beta E mutation in human populations.