Background: The frequency of multiple sclerosis (MS) in Greece remains speculative, as data from many parts are still lacking. Objective: To estimate trends in MS prevalence and annual incidence in western Greece from January 1, 1984 to December 31, 2006. Methods: Patients were identified from the patient records of the Department of Neurology at Patras University Hospital in Rion-Patras. Only patients with a definite MS diagnosis according to Poser’s criteria and retrospective application of the McDonald’s criteria were included. We calculated age- and sex-specific prevalence rates for patients living in the study area on December 31, 2006. Annual incidence rates were calculated for the period 1984–2006. Results: The crude prevalence rate of definite MS cases increased significantly in 23 years from 10.1/100,000 recorded in northeastern Greece in 1984 to 119.61/100,000 on December 31, 2006 in western Greece for the 780 cases still alive. The mean annual incidence rate increased from 2.71/100,000 recorded during the period 1984–1989 to 10.73/100,000 in the 5-year period of 2002–2006. Conclusion: The prevalence rates were higher than expected, but closer than in previous surveys conducted in Greece to those reported recently in Sicily and Istanbul. These findings place the area in the high-risk zone.