Multiple sclerosis (MS) predisposition is thought to be influenced by a complex, yet unclear interaction of genetic and environmental factors. Studying ethnically selected populations may reduce genetic and environmental heterogeneities and help clarify the underlying mechanisms of MS susceptibility. Sardinians kept a homogeneous genetic structure and have among the highest MS frequency rates worldwide. Interestingly, MS in Sardinia is linked to otherwise rare HLA alleles. In this light, recent findings from epidemiological and immunogenetic studies of Sardinian MS are presented. Results confirm that, likely due to significant genetic differences at a microgeographic level, even in this homogeneous population MS is immunogenetically heterogeneous and tends to preferentially cluster in some more archaic areas of the island.