AbstractAnalysis of polymorphisms of the β‐globin gene cluster was performed on 12 families and on one unrelated individual of Sicilian origin who carried hemoglobin C (Hb C). Two different haplotypes were found in association with βcSicilian alleles, corresponding to haplotypes I and II previously described in American blacks. In our population, the more frequent one (haplotype I) was linked to the lack of a polymorphicHpal site 3′ to the β gene (13.0‐kb fragment), similarly to haplotype I in blacks, while the less frequent one was linked to a 7.0‐kbHpal fragment attributable to a site that had never been previously described in linkage with βcalleles. In Italy, these two haplotypes have been found in rare cases in association with βAalleles. These findings provide new insights into the origin of Hb C present in Sicily, suggesting that (1) the βcmutation detected in Sicily derived from African black chromosomes and does not represent a new mutation; and (2) Hb C may have originated either by multiple mutational events on separate chromosomes or by mutation in theHpal site 3′ to the β gene in a pre‐exis