The authors analyzed the natural history of multiple sclerosis (MS) before onset to identify the period of susceptibility and exogenous factors that might play a role in causing the disease. Space-time cluster analysis was performed among northern Sardinians, a genetically stable Italian population that showed an increasing risk of MS between 1965 and 1999. Residence changes from birth to clinical onset were recorded for all MS patients with clinical onset between 1965 and 1999 in the province of Sassari. Closeness in space and time was defined as living in the same municipality and differing in year of birth by 1, 2, or 5 years. Analyses were performed for the period from birth to age 25 years or MS onset and in demographic and clinical subgroups. Clustering was substantial in early childhood. Clustering was most marked in the most recent cases, among women, and among patients with early age at onset, a relapsing-remitting course, and in the eastern subarea. No clustering was found when closeness in time was defined as a fixed number of years before onset, which argues against a fixed latency period. Early childhood seemed to be a period of increased susceptibility to MS. This evidence and the increasing incidence of MS in northern Sardinia are compatible with a change in environmental exposure.