Objectives: To estimate the cumulative incidence rate (CIR) of Chikungunya virus (CHIKV)-associated Central Nervous System (CNS) disease during the La Réunion outbreak, and assess the disease burden and patient outcome after three years.Methods: CHIKV-associated CNS disease was characterized retrospectively in a cohort of patients with positive CHIKV RT-PCR or anti-CHIKV IgM antibodies in the cerebrospinal fluid and fulfilling International Encephalitis Consortium criteria for encephalitis or encephalopathy. Neurological sequelae were assessed after three years.Results: Between September 2005 and June 2006, 57 patients were diagnosed with CHIKV-associated CNS disease, including 24 with CHIKV-associated encephalitis, the latter corresponding to a CIR of 8.6 per 100,000 persons. Patients with encephalitis were observed at both extremes of age categories. CIR per 100,000 persons were 187 and 37 in patients below 1 year and over 65 years, respectively, both far superior to those of cumulated causes of encephalitis in the USA in these age categories. The case fatality rate of CHIKV-associated encephalitis was 16.6% and the proportion of children discharged with persistent disabilities estimated between 30% and 45%. Beyond the neonatal period, the clinical presentation and outcomes were less severe in infants than in adults.Conclusions: In the context of a large outbreak, CHIKV is a significant cause of CNS disease. As with other etiologies, CHIKV-associated encephalitis case distribution by age follows a U-shaped parabolic curve.