The Sardinians are an ethnically homogeneous population, having a genetic structure quite different from that of all other Italian and European populations. All epidemiological studies carried out in Sardinia since 1975 indicate that this Mediterranean island shows twice the prevalence of multiple sclerosis (MS) compared to continental Italy, but the size of the Sardinian communities so far surveyed has been too small to draw definitive conclusions. To overcome this draw-back, we have studied the frequency of MS in a well-defined area of north-western Sardinia, with a population of about 270,000 in the 1991 census. Based on 276 MS cases, the prevalence on December 31st, 1991, was 102.6 per 100,000. The incidence, averaging 2 per 100,000 in the period of 1962 to 1971, rose to 5 in the period from 1977 to 1991. The present study confirms the higher frequency of MS among Sardinians compared to other Italian populations. Genetic, linguistic and historical data suggest a role of environmental and genetic factors in determining the notable difference in MS risk between Sardinia and the rest of Italy.