A study on the HLA structure of the Sardinian population was carried out on 551 healthy unrelated families representing all of the island districts. Altogether 2202 HLA-A, B, Cw, DR individual haplotypes and 853 different haplotypes were determined. Cavalli-Sforza and Edwards' genetic distance index for the total of 62 tested alleles showed a modest heterogeneity between one district and another (0.09-0.16). The genetic distance between Sardinians and the rest of the Italian population was 0.23 (0.22-0.26) and progressively increased in comparisons with caucasoids (0.26), negroids (0.34) and mongoloids (0.41). Sixty-three two-locus haplotypes with a high positive linkage disequilibrium were observed in our family sample. The percentages of two-locus haplotypes in LD shared with other populations turned out to be 45% with caucasoids, 20% with negroids and 10% with mongoloids. The distribution of the A, B, Cw, DR haplotypes is shown with 673 of them represented only once or twice, and 10 (1.2%) 14-322 times each. Of the latter, 8 are extended haplotypes, 6 of which characterize the Sardinian population. The analysis of our data suggests that the present-day Sardinian population is the result of a superposition of different populations, mainly consisting of caucasoids on a pre-caucasoid paleo-Mediterranean substratum.