The islands of Sicily and Malta have very different prevalence rates for multiple sclerosis (MS): at least 44 per 100,000 in Sicily and only 4 per 100,000 in Malta. In Northern Europe, MS is associated with HLA-DR2/Dw2. The other components of the commonest DR2-containing haplotype of this region, HLA-A3-B7-DR2-Dw2, also tend to be present at higher frequency in MS patients. HLA Class I and II antigen frequencies and associations in controls and MS patients from Sicily and Malta were studied to discover whether they might account for the difference in MS prevalence. In Sicilian MS patients, DR2 is increased in frequency compared with controls and four out of five DR2-positive patients also type as Dw2. In the Maltese population, DR2 is present at high frequency but approximately half of the DR2 positive individuals do not type as Dw2 so that DR2 is probably most commonly present as part of Class II haplotypes other than those commonly associated with MS. Additional differences in HLA profile of the Sicilian and Maltese populations were found when HLA-A, -B, and B-DR antigen associations were examined. Therefore, some of the difference in MS prevalence might be explained by genetic factors.