From epidemiological data obtained over more than 20 years by surveys conducted in different parts of Sicily, it is evident that Sicily is a high-risk area for multiple sclerosis (MS). This is in sharp contrast with the gradient hypothesis. High frequencies have been found in different parts of the island having different geoclimatic features, but at least two cities (Monreale and Enna) had had a prolonged Norman domination. This is in agreement with the hypothesis that MS originated in Northern Europe and spread around the world throughout the raids of the northern peoples. The increase in frequency estimated by follow-up and incidence studies is well established and is only in part linked to the improvement in diagnostic techniques. Finally, it is noteworthy that in the islands of Malta, a few sea miles away from Sicily, the MS prevalence rates are in the range of 4-8 cases per 100000 persons. This occurrence represents a natural model to investigate MS etiology through analytic studies and genetic analyses.