We detected Hb D-Los Angeles [beta 121(GH4)Glu-->Gln], the most common hemoglobin variant after Hb S and Hb Lepore-Boston, in six unrelated families in Southern Italy. Ten patients were studied; eight patients were heterozygotes and two were compound heterozygotes for the hemoglobin variant and the beta-thalassemia codon 39 (C-->T) nonsense mutation. The beta-globin gene sequence was characterized by polymerase chain reaction direct sequencing; restriction fragment length polymorphisms were defined by Southern blot analysis. The gene variant, due to the GAA-->CAA substitution at codon 121, was found in association with the 5' subhaplotype [+ - - - -] and the beta-globin gene framework 1; in addition, it was found to be associated with the absence of Ava II/phi beta and Xmn I/5'G gamma, and with the presence of Hpa I/3' beta. This restriction fragment length polymorphism haplotype is common in the Mediterranean area as well as in other populations. The findings are equally compatible with an independent origin in the Mediterranean area or with origin in Asia and subsequent spread to Italy.