Detailed studies of the natural history of untreated multiple sclerosis (MS) have been carried out in London, Ontario, Canada, over the past generation. There are now some 25,000 patient-years of follow-up in a cohort of slightly more than 1,000 individuals. From the data, it is clear that a number of factors are associated with long-term outcome of the disease. The Ontario database reveals several prognostic variables that are clinical in nature, which can be used to evaluate prognosis in any clinical subtype. The most important factors include the development of a progressive deficit and time to onset of progressive deficit. In addition, and independently, a high number of relapses in the first and second year is associated with poor long-term outcome, as is the development of early unremitting disability. An important question is whether or not primary-progressive (PP) MS represents an independent entity separate from secondary-progressive (SP) MS. No specific category of PP disease is distinguishable from SP disease using available clinical measures. There is reason to believe that magnetic resonance imaging (MRI) activity (when appropriately controlled for other unequally distributed factors, such as age) will be found to be very similar.